2005-12-02

A Shot to Stop Diabetes in Mice

Intervention in Immune Regulation Can Prevent Onset of Type-1 Diabetes

Some forms of diabetes could feasibly be prevented. Scientists at the German Research Centre for Biotechnology (GBF) in Braunschweig recently were able to do just that in experiments with mice. Animals with a congenital susceptibility for Type-1 diabetes remained healthy when researchers treated them with an immune regulator shortly after birth. The substance used prevented the immune systems in mice from mistakenly attacking one of their own molecules found in the pancreas of the animals. The findings of the research group have been published in the latest issue of the U.S medical journal, Diabetes.
Type-1 Diabetes is an autoimmune disease triggered by a malfunction of the body's immune defenses. The immune system erroneously identifies certain structures in the body as "foreign objects" and attacks them. In the case of Type-1 diabetes, these "foreign objects" are insulin-producing Langerhans cells in the pancreas.
In one strain of mice, susceptible to this disease from birth, the researchers in Braunschweig moved to prevent this effect from the beginning. "Under certain circumstances the immune system can be retrained," says GBF scientist Dr. Dunja Bruder. "It can become accustomed to substances that it would normally attack with a defensive immune reaction." A decisive role is played in this process - known as immune tolerance – by so-called dendritic cells, or DCs. This cell type, which is prevalent in the lymph nodes, is specially designed to present molecular structures to the more aggressive cells of the immune system and to "teach" them which of these molecules should be attacked and which should be tolerated. Some DCs have a restraining, others a stimulating, effect on the immune system.

Promising new therapy possibilities

Dr. Bruder and her research colleagues at the GBF turned their attention to the "restraining" DCs. The cells were targeted with the help of an antibody. They attached the protein molecule responsible for the autoimmune reaction in the pancreas of the mice to the antibody. What they found was that the DCs apparently presented this molecule to the other immune cells and the immune system learned specifically to suppress the undesirable defensive reaction. "The mice treated in this way," notes Dr. Bruder, "did not develop diabetes." The antibody with the attached protein had been injected into the mice on several occasions after birth.
The work group leader, Prof. Jan Buer, stresses that the findings as yet cannot be directly transferred to humans because the molecule studied in the mice strains is not the same one that triggers diabetes in people. However, Dr. Buer is confident that the process could at some point be used as the basis for a diabetes prophylaxis in humans. "It is possible that the same principle might be able to prevent other autoimmune ailments," says Buer.



Additional Information

A detailed description of the findings can be found in the original article: D. Bruder, A.M. Westendorf, W. Hansen, S. Prettin, A.D. Gruber, Y. Qian, H. v. Boehmer, K. Mahnke, J. Buer. On the edge of autoimmunity: T cell stimulation by steady state dendritic cells prevents autoimmune diabetes. Diabetes. 2005 Dec; 54(12):3395-3401.
Photo material can be viewed or downloaded at: www.gbf.de/presseinformationen



Photo legend

Dnmaus02.jpg:
Dr. Dunja Bruder and one of her diabetes-prone mice.
Photograph: GBF/Hübner
DCundT2.jpg:
T cells (red) interacting with a dendritic cell.
Photograph: GBF/Rohde
tzellen.jpg:
T cells (blue) interacting with a dendritic cell.
Photograph: GBF/Rohde

2006-03-09

A Deep Sea Brine Interface Teeming With New Life

Newly Discovered Bacteria Form a Complex Ecosystem

In the latest issue of the prestigious science journal, Nature, a European team reports the discovery of diverse new microbial communities in an unusual deepsea environment. Several so-called brine “lakes”, distinct salt-saturated water bodies underneath the water column of the Mediterranean Sea, formed thousands of years ago by dissolution of rock salt exposed by geological events. These “lakes under the sea” are 3-4 km below sea surface and represent extreme environments for living organisms: they are characterized by high pressure (400x atmospheric pressure) and salinity (10x saltier than seawater), and lack oxygen. Because of their high densities, brine lakes do not mix with the overlying water and thus have been isolated from the rest of the biosphere for a very long time. Professor Timmis of the German Research Centre for Biotechnology (GBF) in Braunschweig, a member of the team that explored the brine lakes, explains: “Despite the fact that such environments exist on our planet, we know so little about them that their exploration is as exciting as interplanetary missions. The big question was: do they contain new forms of life?” In order to answer this question, several expeditions to sample the basins have taken place in the framework of the BIODEEP Project funded by the European Commission.

Impressive Variety
In their Nature paper, the BIODEEP team reports the discovery of flourishing diverse communities containing novel microbes in the brine lake:water column transition zone of the Bannock Basin located off the coast of North Africa. The diversity and high populations of microbes in an environment hostile to life surprised the researchers. Apparently, the high density of the brine traps dead organisms and their products drifting down through the water column to create a transition zone high in organic material that can support a rich community of salt-and pressure-tolerant microbes specialized to live without oxygen. Moreover, the steep salinity and oxygen gradients across the interface create a sequence of discrete and distinct environments, some just centimetres thick, and each with different concentrations of compounds like sugars, sulfates, nitrates and manganese (compounds used in place of oxygen to extract energy from food), that provide diverse habitats for distinct communities: a stratification of habitats and communities. Many new microbes, including 4 new Divisions of Bacteria unrelated to any known organisms, were discovered, and 84 could be isolated in culture for further study.

“Our current investigations indicate that phylogenetic diversity reflects functional diversity, that is: new organisms have new activities and make new bioproducts with potential for medical and chemical applications”, says Timmis. “The discrete stratified habitats of the brine lake interfaces constitute exceptional conditions in which novel organisms have evolved. Systematic exploration of these and other extreme environments, and characterization of the biological properties of the new organisms found, will undoubtedly lead to important discoveries about life processes and interesting new biotechnological applications.”


Additional Information for the Media
More detailed information can be found in the original article: D. Daffonchio, S. Borin, T. Brusa, L. Brusetti, P. van der Wielen, H. Bolhuis, M. Yakimov, G. D’Auria, L. Giuliano, D. Marty, C. Tamburini, T. McGenity, J. Hallsworth, A. Sass, K. Timmis, A. Tselepides, G. de Lange, A. Hübner, J. Thomson, S. Varnavas, F. Gasparoni, H. Gerber, E. Malinverno, C. Corselli & Biodeep Scientific Party: Stratified Prokaryote Network in the Oxic-Anoxic Transition of a Deep-Sea Halocline. Nature, 9 March 2006, Vol 440, No. 7081, pp 203-207.

2006-05-02

Beating Bacteria with Bacteria

New Antibiotic Tackles Multi-Resistant Germs

There is new hope in the battle against bacterial pathogens resistant to “last line of defence” drugs. Scientists at the German Research Centre for Biotechnology (GBF) in Braunschweig have discovered a novel – and natural – substance that inhibits the growth of such bacteria. This new substance, which goes by the name MMA, or 7-O-malonyl-macrolactin A, has proven effective against several multi-resistant germs. Its discovery is published in the latest issue of Antimicrobial Agents and Chemotherapy.
“Multi-drug resistance in infectious agents, particularly in hospitals, is one of the most important challenges facing medicine today”, explains Professor Timmis, Head of the Division of Microbiology in the GBF. “The widespread non-clinical use of antibiotics as growth promoters in animal feeds and, more recently, in aquaculture, has resulted in the rapid evolution and spread of resistance to a wide range of antibiotics in pathogenic microbes, and compromised the clinical management of infections. Moreover, the exceptional success of early antibiotics in the treatment of infections led to complacency and a focusing on other diseases and treatments. As a result, the pipeline of new antibiotics is practically empty, so that the prospects of new antibiotics effective against current multi-resistant bugs are bleak.”
The new antibiotic, MMA, was discovered through a GBF research programme to explore new microbial diversity for new drugs, and involved a collaboration with Indonesian colleagues. It is produced by a new strain of the soil bacterium Bacillus subtilis, which may produce it as an ecological weapon to compete with other bacteria in the soil. According to Professor Timmis, “more than 90% of thus far unexplored biodiversity is microbial diversity, so the microbial world represents a treasure chest for future discoveries of new drugs and other useful bioproducts”.

MMA versus MRSA

GBF scientists see a promising future for MMA, which not only inhibits MRSA, the notorious strain of methicillin-resistant Staphylococcus aureus, but also vancomycin-resistant enterococci (VRE), both of which cause potentially lethal infections in hospitalized patients. MMA inhibits cell division by the bacteria, so they are unable to divide and spread. "Antibiotics have been our strongest weapon against bacterial pathogens," explains Dr. Gabriella Molinari, Head of the Drug Discovery Unit of the GBF. " The acquisition of new weapons to either kill or inhibit bacterial growth is one of the greatest imperatives in medicine, so MMA and other lead molecules spinning-off our natural products drug discovery program are promising tools in the fight against infections ”. However, it will take a few more years before it is known whether MMA can find its way into the clinic. "The substance first needs to be studied more closely and thoroughly tested," notes Dr. Molinari, “and ultimately clinical trials will be needed to show whether MMA is really suitable for human use."



Source Material for the Media

Further information is provided in the original article: M. Romero-Tabarez, R. Jansen, M. Sylla, H. Lünsdorf, S. Häußler, D. Santosa, K. Timmis, G. Molinari. 7-O-Malonyl Macrolactin A, a New Macrolactin Antibiotic from Bacillus subtilis Active against Methicillin-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococci, and a Small-Colony Variant of Burkholderia cepacia. Antimicrob. Agents Chemother. 2006 50: 1701-1709. (http://aac.asm.org/)



Photo legend

MMA01:
GBF scientist Dr. Gabriella Molinari
Photograph: GBF/Bierstedt


MMA02:
Searching for new antibiotics: A test for substances that inhibit the growth of bacteria.
Photograph: GBF/Bierstedt


MMA03:
A dangerous resistant pathogen: Staphylococcus aureus.
Photograph: GBF/Bierstedt

2006-05-19

Shampoo consuming Bacteria

Why Pseudomonas is able to withstand attacks of hygiene

The pernicious bacterium Pseudomonas aeruginosa is able to persist in the human respiratory tract for long periods of time and also frequently causes acute infections in open wounds especially following open surgery. It is able to resist common house-hold detergents making it difficult to eradicate by normal hygiene routines.


Scientists from the German Research Centre of Biotechnology (GBF) and the Hannover Medical School (MHH) have now identified the reason why these bacteria are resistant to detergents: Pseudomonas secretes an enzyme SdsA that cleaves SDS or Sodium dodecylsulfate - a constituent of many foaming personal hygiene products such as toothpaste, shampoo and shower gels. SDS is a detergent that kills most bacteria by dissolving their surrounding membrane. Pseudomonas aeruginosa protects itself by secreting SdsA, which cleaves and inactivates SDS. The team that includes scientists from Göttingen and Darmstadt in addition to those from Braunschweig and Hannover has now published its results in the prestigious scientific journal Proceedings of the National Academy of Sciences USA (PNAS).


Shampoo as a favorite dish


Using X-ray crystallography, the scientists solved the three-dimensional structure of SdsA at near atomic resolution permitting them to watch the enzyme as it cleaves SDS. The researchers discovered that the bacteria absorb the resulting fragments of SDS utilizing them as nutrients.


The ability of Pseudomonas to resist SDS and to utilize the cleavage products probably explains why this pathogen is frequently found in locations that we prefer to maintain in pristine condition: these include bathroom basins, dishwashers and shampoo bottles. "Apart from the risk to human health, the economic damage can be daunting", concludes GBF group leader Dr. Wolf-Dieter Schubert, "Recalling contaminated products is not only costly, but is particularly damaging to the carefully maintained image of the companies involved."


While SdsA helps to make Pseudomonas dangerous to humans, the cleavage of SDS has its beneficial aspects as well. The bacteria, which live in rivers and even sewage treatment plants, destroy SDS and similar contaminants introduced into the environment as part of normal human behavior.


Information for the media


Detailed Information provided by the original article: G. Hagelüken, T. M. Adams, L. Wiehlmann, U. Widow, H. Kolmar, B. Tümmler, D. Heinz, W.-D. Schubert: The crystal structure of SdsA1, an alkylsulfatase from Pseudomonas aeruginosa, defines a third class of sulfatases. Proceedings of the National Academy of Sciences, 2006, Vol. 103, N. 20, pp. 7631-7636.




Photo legend


Sdsa_01
The three-dimensional structure of the SDS-degrading enzyme SdsA from the bacterium Pseudomonas aeruginosa: The structure is presented as a ribbon diagram. The colored dots in the background represent individual atoms in SdsA crystals.


Sdsa_02
An abstract display of the three-dimensional structure of SdsA: The pale-yellow spheres represent zinc-ions that are essential for the cleavage of the detergent SDS. The structural regions of the protein – each of which has a distinct function – are marked in different colors: blue (catalysis), orange (binding suitable molecules to pass on to the catalytic domain) and green (binding two molecules of SdsA into a functioning unit.)


Sdsa_03
The catalytic site of the enzyme SdsA: Two zink ions (yellow spheres) activate two water molecules (red dots), so that they can attack and split the SDS-molecule – held by orange-colored amino acids. The products of the reaction (pale blue/green) at first stay bound to the enzyme before being released to the surrounding.

 

MWPI_2005_Lab19_dhs  (Photo: GBF /Bierstedt)
GBF scientist Wolf-Dieter Schubert in his lab.

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2006-05-05

The Taming of the Pathogen

The drug AZM disrupts the information flow between Pseudomonas bacteria

The drug, azithromycin (AZM), has been found to curb pathogenic bacteria. AZM combats bacteria in the Pseudomonas aeruginosa family, which can be especially dangerous for people with respiratory ailments. Scientists at the German Research Centre for Biotechnology (GBF) in Braunschweig have discovered that AZM prevents these bacteria from becoming aggressive and destructive. AZM blocks the mechanism used by the bacteria to "measure" how many of them there are in a particular environment. Unaware of their numbers and how strong they've already become, the pathogens, as a result, delay their big attack.
Pseudomonas aeruginosa can trigger persistent and troublesome lung infections. The bacteria can even become a serious and frequently deadly threat for people suffering from cystic fibrosis (CF), a congenital disease that adversely affects respiratory functions, impeding, for example, the clearing of the lungs of particles and bacteria embedded within the bronchial mucous. For Pseudomonas aeruginosa, the viscous lung secretions of CF patients are an ideal habitat. "Many people with this disease become infected with Pseudomonas aeruginosa and never get rid of it," explains GBF researcher, Dr. Susanne Häussler. "Pseudomonas aeruginosa for them is the most common cause of death." For many, catching this pathogen means having to live with it. "Antibiotics don't help," says Dr. Häussler, "because Pseudomonas becomes virtually entrenched in the thick bronchial mucous of CF patients."
AZM, which belongs to the macrolide group of drugs, is incapable of killing Pseudomonas aeruginosa, but helps to keep the pathogen relatively benign, preventing it from moving into a more antagonistic phase where it would begin attacking and destroying large sections of lung tissues - a circumstance that usually is fatal for cystic fibrosis patients.
The mechanisms involved in this process have now been clarified by Susanne Häussler and her research colleagues and published in the most recent issue of the Journal of Antimicrobial Agents and Chemotherapy. "AZM disrupts the bacteria's so-called quorum sensing mechanism," explains Dr. Häussler, "a mechanism used by them to determine their population density." Only when the bacteria have reached a certain population density they become virulent. They no longer appear satisfied to grow unnoticed, but switch instead into a more aggressive mode, directly confronting the human immune system. Häussler is confident that understanding this mechanism could help in the long term to search for new agents that combat chronic infections with Pseudomonas aeruginosa. "In many cases," says the GBF researcher, "it is nearly impossible to eradicate all the Pseudomonas bacteria found in the lung of a cystic fibrosis patient." "But," she adds, "we can stabilize a patient's condition and improve the chances if we look specifically for substances that disrupt the pathogen's quorum sensing abilities. And, if the immune system is given enough time, it has a chance to combat these less virulent bacteria. can in some cases combat the bacteria."

Additional Information for the Media

Original article: Y. Nalca, L. Jänsch, F. Bredenbruch, R. Geffers, J. Buer, S. Häussler: "Quorum Sensing antagonistic activities of Azithromycin in Pseudomonas aeruginosa PAO1: a global approach." Journal of Antimicrobial Agents and Chemotherapy, May 2006, Volume 50, Issue 5.
Photo material on this subject is available at: www.gbf.de/presseinformationen


Photo legend


„Pseudom01“:
The most common cause of death among people suffering from cystic fibrosis: Pseudomonas aeruginosa
Photograph: GBF/Rohde

„QuorumTeam”
“Tracking the communication pathways of Pseudomonas bacteria: GBF scientists Dr. Yusuf Nalca and Dr. Susanne Haeussler.
Photograph: GBF/Gramann”

2005-09-22

Life-sustaining stuff

ALAS, scientists at the GBF reveal the structure of a life-sustaining enzyme

Heme is the pigment responsible for the red colour of blood. All humans and animals need heme because it alone transports life-sustaining oxygen from the lungs to the tissues of the body. Scientists of the GBF and the Technical University in Braunschweig have resolved the 3-dimensional structure of the enzyme that catalyses the first step in the synthesis of heme. “This project completes a page in the history of science,” explains Dirk Heinz, head of structural biology at the GBF. “ALAS (short for ‘5-aminolevulinate synthase’) was the last remaining enzyme in heme synthesis for which the 3-dimensional structure was not known.” The results are now being published in the scientific EMBO Journal.
Production of heme in humans and animals works like an assembly line. Ten separate enzymes are involved. Each receives a precursor molecule from the preceding enzyme, modifies it in a predetermined way, and passes it on to the next enzyme in the queue. “ALAS is particularly important,” says Dieter Jahn, professor of microbiology at the Technical University, “because it is the first enzyme in the process. If it malfunctions, the entire process of heme synthesis is affected, resulting in severe anaemia”.
Dysfunction of ALAS, most often due to genetic defects on the X-chromosome, causes a particularly severe form of anaemia. Overall, a shortage of heme restricts the supply of oxygen to body tissues causing common symptoms including pale skin, tiredness and lack of concentration. In this case, they are, however, combined with the accumulation of toxic levels of iron that cause acute organ damage. “The new findings should help affected patients, in the long-term,” says Wolf-Dieter Schubert, group leader at the GBF. “The structure of ALAS will aid our understanding of this form of anaemia, will help to explain the symptoms, and will eventually enable us to improve its treatment”.
The structural analysis of ALAS was partly made possible by chance: Nature tends to stick to tried-and-tested biological principles for billions of years. Apart from humans, ALAS is also found in the evolutionary ancient group of proteobacteria. These primitive organisms invented the process of producing heme and related pigments about 3.5 billion years ago, when life itself had barely been established. The scientists could therefore use bacterial ALAS, which is very similar to the human form but much more stable, to analyse the structure.



Information for the media

Detailed information may be found in the original article:
Isabel Astner, Jörg O. Schulze, Joop van den Heuvel, Dieter Jahn, Wolf-Dieter Schubert and Dirk W. Heinz: Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans. The EMBO Journal (2005) 24, 18, 3166-3177



Photo legend

ALAS: Cartoon-type diagram of an ALAS-dimer. One subunit is shown in colour, the second in grey.
ALAS mutiert: Each mutation in the enzyme ALAS that is known to cause the anaemia in humans is represented by a coloured sphere.

2005-08-26

Vitamin D puts a brake on activated macrophages

How a newly discovered mechanism keeps inflammation under control

When macrophages, the first line defender cells of the immune system become activated, they produce an inhibitor, which acts back on them to suppress their activity. This has been revealed by the work of scientists at the German Research Centre for Biotechnology (GBF) in Braunschweig together with colleagues at the Hannover Medical School and at the University of Münster. The suppressor turned out to be an “old acquaintance”: vitamin D3, already well known, particularly for its role in bone metabolism. The scientists have now published their findings in the journal Blood.

Macrophages are the immune system’s “body guards”. They are patrolling the body’s blood and lymph system eating up everything that might be foreign or dangerous for the body – whether these are bacteria, breakdown products or foreign particles. The ingested material is then presented to other specialized immune cells, which determine whether or not these particles constitute a danger for the organism.

If a danger is sensed, interferon-γ is released in response – a chemical alarm signal, which acts back on the macrophages and stimulates them. They now accumulate at the site of the danger signal and employ their whole arsenal of biochemical weaponry against the invader. This includes among others hydrogen peroxide, which the macrophages use to kill and neutralize ingested pathogens. The organ or tissue where the defender cells accumulate and go into action is referred to as being “inflamed” by the doctor.

According to the discoveries of the GBF researchers however, as macrophages join this battle they can release vitamin D3, which begins to rein them in after a while and reduces their aggressiveness. A possible explanation for this mechanism is that it functions as a “self-regulatory device of the immune system” suggests the former GBF Ph.D. student, Dr. Laura Helming, who discovered the mechanism while working on her Ph.D. thesis and who is working now as a postdoctoral fellow at Oxford University: “The purpose may be suppression of the inflammatory reaction, before it overshoots the mark”. If this would happen, it could prove to be more dangerous to the organism than the invader itself. Uncontrolled, activated macrophages can cause severe damage and even total destruction of body tissue. Thus, the incorporated vitamin D3 brake makes sure that the body’s own body guards are kept back soon after their activation.

Project leader, Dr. Andreas Lengeling, believes that this discovery may well have medical applications: “The better we understand this mechanism, the easier it will be to develop therapies for chronic inflammatory disorders”, he says.



References for the media

Detailed information can be obtained from the original article: L. Helming, J. Böse, J. Ehrchen, S. Schiebe, T. Frahm, R. Geffers, M. Probst-Kepper, R. Balling und A. Lengeling: 1α,25-dihydroxyvitamin D3 is a potent suppressor of interferon-γ mediated macrophage activation. The article is now available online as a first edition publication at the website of the Journal Blood (http://www.bloodjournal.org/papbyrecent.shtml).

Photographic material can be found at www.gbf.de/presseinformationen



Photo legend

The picture shows infected macrophages battling against Listeria, a pathogenic bacterium that can multiply inside the cell. For defense against infection, balanced macrophage activation is essential. Here, the messenger substances, interferon-γ and vitamin D3, play important roles, as GBF researchers have now discovered.

Photo: GBF

2005-06-22

Versatile Bacteria Toxin

How Pathogens Manipulate Host Cell Membranes for their Own Purposes

Some aggressive bacteria are capable of penetrating human body cells and then destroy them from the inside. Just how this is done, for example, by the food germ, Listeria monocytogenes, has been studied by a team of scientists from the German Research Centre for Biotechnology (GBF) in Braunschweig and the University of Giessen. Their findings: the bacteria secrete a toxin that causes major alterations to the surface of host cells. These pathogens are then able to overcome the cell's defence mechanisms, making it easier for them to penetrate the cell. The results of the study have been published in the journal, Cellular Microbiology.

The primary boundary of life is defined by the cell membrane, an oily sheet made up of various fat molecules and proteins. In order to integrate and communicate important signals from the “outside world” into the cell, the proteins and fat molecules which make up the cell membrane have to work in a coordinated fashion. For that, some of the proteins and fat molecules are concentrated into viscous assemblies called "rafts". "These rafts," explains GBF work group leader, Dr. Siegfried Weiss, "are the key for many biochemical processes since they provide anchorage to many important regulatory molecules. Rafts are therefore in essence the ´trigger spots` where the cell processes signals received from the outside."

These key areas are the focus of Listeria monocytogenes. The bacteria produce a cell toxin that induces several small raft regions on the cell's surface to aggreagate together into a big, "super raft". "By this mechanism, the bacteria are able to activates the the rafts-associated regulatory molecules," says GBF junior scientist Nelson Gekara, "and these trigger different responses in the cell which for intance leads to a block in the cell´s defense mechanisms, much to the advantage of the invading bacteria." Furthermore, the rafts also function as a port-of-entry for the pathogens.

Listeria monocytogenes enters the human body from contaminated foodstuffs and can trigger intestinal ailments. People with weak immune systems are especially susceptible and therefore prone to the characteristic complications such as meningitis and abortion which stem from such infections.

"The mechanism with which Listeria attacks the surface of the targeted cell can tell us a lot about basic principles of infection," emphasizes Weiss. "We suspect that other, medically far more important pathogens proceed in a similar manner – for example, Streptococci or Bacillus anthracis, the anthrax pathogen." Weiss hopes that the Listeria cell toxin can help scientists better understand the function and importance of rafts on human cell surfaces.



Additional information

More information can be found in the original article: Gekara, N., Jacobs, T., Chakraborty, T. and Weiss, S. "The cholesterol dependent cytolysin Listeriolysin O aggregates rafts via oligomerization".
A pre-publication online version of the article is available on the Web site of the journal Cellular Microbiology: http://www.blackwell-synergy.com/loi/ch

Photo material available at: www.gbf.de/presseinformationen


Legends:

Gekara_Weiss_02.jpg: GBF work group leader Dr. Siegfried Weiss (left) with Nelson Gekara study the bacteria Listeriolysin O and its effect on human cells.
Photo: GBF/Hübner

Listeria_MZ_01-03.jpg: View of rod-shaped cells of the bacteria, Listeria monocytogenes, attaching themselves to a human cell.
Photo: GBF/ Rohde

LLO and ERMp picture1-2.jpg: The impact of the bacteria toxin, Listeriolysin O (LLO), here in red, on the cell membrane. The protein, ERM, which plays an important role in transport processes inside the cell is shaded green in this coloration technique, but only when active. The fireworks of green signals illustrates that LLO is preparing the cell membrane for a transport process through the membrane, the prerequisite for bacteria to enter the cell.
Photo: GBF/Nelson Gekara

2005-03-08

Malicious at the turn of a button

"Molecular Switch“ turns food bacteria into dangerous germ

How do harmless bacteria turn into dangerous pathogens? This is a question researchers at the German Research Centre for Biotechnology (GBF) in Braunschweig are currently investigating. Using the common food germ, Listeria monocytogenes, the scientists have identified a mechanism – a protein molecule called PrfA – that under certain conditions can switch on the genes that make the bacteria aggressive. Listeria monocytogenes then invades human cells in the intestinal mucous membrane, spreads and multiplies. GBF scientists now describe the three-dimensional structure of the PrfA protein for the first time. Their studies show that PrfA can turn itself on and off biochemically, essentially turning Listeria into a malicious germ at the "push of a button".

The bacterium, that enters the human body in association with contaminated food, can trigger intestinal and other diseases. In some cases, severe complications result. Meningitis and miscarriages are just two of the most severe afflictions patients may suffer. People whose immune system is impaired are particularly at risk as the pathogen may attack inner organs and spread throughout the body. Such systemic infections may result in death of the patient.

The first phase of listeriosis is the attachment of Listeria to the surface mucous membrane of the human intestinal tract, followed by a penetration into the intestinal cells. To invade and survive in the host cell environment Listeria monocyotgenes must activate special genes. The mechanism for this is the protein PrfA, the "main switch" that turns otherwise innocuous bacteria into aggressive germs. "In most strains of Listeria, PrfA is activated only under certain conditions; for example, conditions that prevail in the human intestinal tract," explains Professor Dirk Heinz, department head at the GBF. On the other hand, a few strains carry a slightly altered PrfA. As a result, these bacteria are locked into a permanently "aggressive mood" producing invasion-promoting proteins continuously. Ultimately, these proteins prove harmful to the bacteria themselves, which is why the constantly aggressive Listeria strains have not been able to win the upper hand in nature.

"We have now studied and compared the structures of normal PrfA and the modified, constantly activated variant," says Marina Eiting, a GBF researcher involved in the project. after comparing these with similar proteins in other bacteria, Eiting and her colleagues now believe that PrfA is probably transformed into its active form by a small as yet unknown, signal molecule – a form that is very similar to the constantly active PrfA variant.

"Possibly the signal molecule originates in the human cell," postulates Prof. Heinz. For GBF researchers this is a question worth investigating further. "If we find the mechanism responsible for switching on the aggressive bacterial behaviour, then we may also find a way to turn it off," says Heinz. A feasible option could be, for example, to block the binding site of the signal molecule with a similar, but harmless, molecule. "This sort of discovery," he emphasises, "could certainly be used for other even more medically important pathogens."



Additional Information

Further information can be found in the original article: Eiting, M., Hagelüken, G., Schubert, W.-D., Heinz, D.W.: The mutation G145S in PrfA, a key virulence regulator of Listeria monocytogenes, increases DNA-binding affinity by stabilizing the HTH-motif. A pre-publication online version of the article is available on the website of the journal Molecular Microbiology (http://www.blackwell-synergy.com/links/doi/10.1111/j.1365-2958.2005.04561.x/full/)

 


Legends:

Heinz_et_al_01.JPG: Structure determination of molecules by X-ray crystallography: GBF scientists from left Professor Dirk Heinz, Gregor Hagelüken and Marina Eiting. Photograph: GBF / Ammerpohl

Listerie_02.JPG: Cells of Listeria monocytogenes – coloured in yellow and orange – on the surface of a human cell. Photograph: : Manfred Rohde/GBF

 

2006-07-03

The Immune Cells with the Built-In Blocker

The molecule GPR83 can turn killer cells into peacemakers

Researchers in Braunschweig have tracked down a natural inhibitor mechanism in our immune system. The molecule, known as GPR83, can block over-reactions by our immune system's defenses before these damage body tissues, according to scientists at the German Research Centre for Biotechnology (GBF). GPR83 manages to do this by switching immune cells from their aggressive defense posture into a more docile mode. A breakdown of this mechanism, the researchers say, could play a role in auto-immune diseases, such as rheumatoid arthritis or Type-1 diabetes, as well as in host defense against severe infections. A summary of the findings can be found in the most recent issue of the Journal of Immunology.
A constant back-and-forth between the encouragement and inhibition of signals directs the activities of the human immune system. When bacteria or viruses enter the human organism, immune cells must be in a position to act swiftly and effectively against the invaders. That is why immune responses have the tendency to quickly accelerate into overdrive with self-amplifying mechanisms, even when the threat is minor. In the case of a false alarm, this can lead to an attack on the body's own tissue and, in turn, cause serious damage. For this reason, it is indispensable that the immune system has specific inhibitor mechanisms to subdue over-reactions.
T cells are among the most potent defenders of the immune cells, which among others things can kill infected cells. "Some T cells appear to possess a built-in blocker on their surfaces," explains GBF researcher Dr. Wiebke Hansen. "The molecule GPR83 serves as a receptor – as a kind of antenna – that responds to strong immune system over-reactions. When GPR83 is activated, the T cells do not become killers but are transformed into docile regulatory T cells – TREGs for short," says Dr. Hansen. From then on, they induce an immune tolerance by deactivating other T cells. "However, just who in the body is stepping on the brakes, and under what circumstances, still has to be clarified more thoroughly," she says.
For the Braunschweig researchers, studying the functions and impact of the GPR83 T cell inhibitor is promising. "If, at some point, we are able to find a way to stimulate GPR83 with drugs, this could be used to treat over-reactions or malfunctions of the immune system; for example, in the case of auto-immune diseases and chronic inflammations," notes the GBF work group leader, Prof. Jan Buer. By contrast, a targeted blocking of GPR83 would make the immune system more aggressive, and that, says Buer, could some day be interesting for treating severe infections, or for tumor therapy.


Source Material for the Media:

Additional information is available from the original article: W. Hansen, K. Loser, A. Westendorf, D. Bruder, S. Pförnter, C. Siewert, J. Huehn, S. Beissert and J. Buer: GPR83-overexpression in naїve CD4+CD25- T cells leads to the induction of Foxp3+ regulatory T cells in vivo. Journal of Immunology 2006, Vol. 177, pp. 209-215.

Photo material on this topic can be found at:

Photo legend


Nrp_Team:
Studying the cells of the immune system and their interactions: Scientists from the research group "Mucosal Immunity" at the GBF.
From left to right: Prof. Dr. Jan Buer, Dr. Wiebke Hansen, Dr. Dunja Bruder.
Photograph: GBF/ Ammerpohl.

DC mit T_Zellen:
T cells (red) interacting with denritic cells.
Photograph: GBF / Manfred Rohde

 

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2006-07-12

A New Name for the GBF: Helmholtz Centre for Infection Research

Invitation to the Press on July 18, 2006 at 1 pm

The German Research Centre for Biotechnology (GBF) in Braunschweig has a new name. From July 18, our name will be Helmholtz Centre for Infection Research. The change, we believe, reflects more clearly the scientific focus of our institute. Another reason for the switch is to underscore the significance of the brand "Helmholtz Association" in Germany and abroad as the largest German research organization. The Helmholtz Centre for Infection Research is one of 15 research centers with 25,000 employees joined together under the umbrella of the Helmholtz Association.


"In the laboratories of our center, scientists are investigating the mechanisms involved in the transmission of infectious diseases and the defenses against them," explains Prof. Rudi Balling, Scientific Director of the Helmholtz Centre for Infection Research. "The results of our basic research are systematically developed toward medical applications, so we think the actual thrust of our scientific work is expressed much better by the new name," says Balling.


Prof. Jürgen Mlynek, President of the Helmholtz Association, also expects the name change to have a positive effect. "We hope the internationally respected quality research conducted by the Helmholtz Association will, in future, also be mirrored by our name recognition," says Mlynek. "To achieve that, numerous centers of the Association, in the months to come, will be changing their names to include 'Helmholtz' in the title." Mlynek sees the name changes as part of a strategy to sharpen the profile of the research centers to improve their international competitiveness.  "We want to give the centers a better position globally to compete for the best minds and funding," he says.


The name change is also accompanied by a new design. The three rainbow-like arcs in the new logo represent the three core elements of the Helmholtz strategy: to contribute to solving pressing world problems, to conduct research with complex technologies and infrastructures and to promote social and business applications for scientific findings.


Members of the media are invited on July 18, 2006 at 1 pm as part of the renaming festivities that day on the campus of the Helmholtz center in Braunschweig. There will be an opportunity for photographs at around 2:00pm following a flag-raising ceremony to unveil our new banner.



Please take note:


Also on July 18th, the Helmholtz Centre for Infection Research will be opening a new reception building. The campus will then be accessible from Inhoffenstrasse 7. Travel directions can be found at www.gbf.de or www.helmholtz-hzi.de.


2006-07-28

Oil Tanker accidents as a Source of Food

Researchers Decode Genes of Oil-Degrading Bacteria

Oil tanker accidents can result in the release of huge amounts of crude spill into the sea which causes serious ecological and economic damage. Despite the hazard they represent for higher organisms, they constitute "breakfast, lunch and dinner" to oil-eating bacteria. Such bacteria that feed off crude oil, which also emanates from natural seeps from oil fields, have found themselves an energy-rich food source and, in the process, help clean up contaminated environments.

 

 

Together with colleagues from Spain, Italy and the University of Bielefeld, researchers in Braunschweig have, for the first time, decoded the genome of the most important of these oil-degrading microorganisms, Alcanivorax borkumensis. The scientists from the Helmholtz Centre for Infection Research and their colleagues have now published their findings in the journal Nature Biotechnology. They anticipate that understanding the biochemistry of Alcanivorax borkumensis will help in the development of new, effective and environmentally-friendly methods to clean up oil-contaminated bodies of water.

 

 

"Alcanivorax borkumensis is capable of living exclusively off the hydrocarbons present in crude oil," explains Dr. Vitor Martins dos Santos, one of the scientists involved in the project at the Helmholtz Centre for Infection Research. "Now that we have sequenced the genetic material, we can discover how the bacteria manage this feat." - "We already know of a number of marine oil-degrading bacteria," says Dr. Peter Golyshin, the coordinator of this joint research project between partners like the Helmholtz Centre for Infection Research, the University of Bielefeld and the Braunschweig Technical University. "However, several studies have shown that Alcanivorax borkumensis, which was discovered in Braunschweig, is one of the most important worldwide. And after the genome sequencing we know why: these bacteria produce a whole arsenal of very effective oil-degrading enzymes."

 

 

This could turn out to be a very important contribution to efforts to mitigate the ecological damage of oil spills. The biochemical tricks of these bacteria, embedded in the genes, could be used by humans to clean up marine pollution. But not only that: Alcanivorax borkumensis could also help scientists to better understand bacterial survival strategies. "Oil-degrading bacteria form so-called biofilms on the interface between oil and water," notes Prof. Kenneth Timmis, the head of the group at the Helmholtz Centre. "And since microbial biofilms are the principal lifestyle of both beneficial and disease-causing microbes on and in the human body, a deeper understanding of these processes will certainly benefit efforts to improve human health and control microbial infections."

 

Original article:

S. Schneiker, V.A.P Martins dos Santos, D. Bartels, Th. Bekel, M. Brecht, J. Buhrmester, T. N. Chernikova, R. Denaro, M. Ferrer, C. Gertler, A. Goesmann, O.V. Golyshina, F. Kaminski, A. Khachane, S. Lang, B. Linke, A. McHardy, F. Meyer, T.Y. Nechitaylo, A. Pühler, D. Regenhardt, O. Rupp, J.S. Sabirova, W. Selbitschka, M.M. Yakimov, K.N. Timmis, F.-J. Vorhölter, S. Weidner, O. Kaiser, P.N. Golyshin: Genome sequence of the ubiquitous hydrocarbon degrading marine bacterium Alcanivorax borkumensis sheds light on marine oil degradation. Nature Biotechnology, 2006.

 

Background: New name for the GBF

As of July 18, 2006, the German Research Centre for Biotechnology (GBF) in Braunschweig changed its name to "Helmholtz Centre for Infection Research". The new name underscores the main research thrust of the center and more clearly identifies its membership in the Helmholtz Association, Germany's largest scientific organization.

 

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2006-08-15

Reins and Spurs for the Immune System

How Disruptions of T Cell Balance Induce Severe Intestinal Inflammation

A finely tuned equilibrium between aggressive and inhibitive immune cells ensures that the intestinal mucosa remains healthy and functional. Scientists at the Helmholtz Centre for Infection Research in Braunschweig, however, have studied on mice what happens when the normal interaction between these cells is disrupted: severe intestinal inflammation, whose symptoms closely resemble human autoimmune diseases, such as Morbus Crohn or Colitis ulcerosa.

"The intestinal surfaces form a border between the insides of the human body and the outside world, and they present our immune system with a monumental task," explains Dr. Astrid Westendorf, a researcher at the Helmholtz center. "Bacteria and other disease-causing pathogens that attempt to penetrate the body must be vehemently repelled at this point," she says. "On the other hand, nutrients, as well as the body's own cells and molecules, must not induce an immune reaction. Otherwise, a severe inflammation could result which might, in the long term, cause serious damage, and in some cases, even destroy the intestinal mucosa."

 

 

Dramatic Symptoms

This is exactly what happens with so-called Villin HA-mice, which were studied by Westendorf and her colleagues. "These animals belong to a genetically altered strain that possess a molecule known as hemagglutinin, or HA, on the cells of their intestinal mucosa," she says. Westendorf injected these animals with immune cells from the blood of other mice strains that specifically produced immune cells targeting HA. The result: the immune cells attacked the intestinal surface and induced dramatic symptoms similar to those of patients with chronic intestinal inflammation.

 

 

A Surprising Tolerance

When these two strains of mice are cross-bred, however, they produce something astonishing: "The progeny have both the HA on the intestinal surface as well as the special immune cells against HA in their blood, and yet, they remain healthy," notes Westendorf. The reason for this phenomenon, known as "immune tolerance", is probably the so-called regulatory T cells, or TREG , which are specific inhibitors of the immune system that shut down other defense cells before they go too far with their attacks and cause harm to the body. "These TREG must have developed in the animals in the course of their lives," says Dr. Westendorf. They keep the defense cells in check, most of which are the CD4+ or CD8+ type T cells, since these would otherwise attack the always present components of their own intestinal surface.

 

 

Complex Interaction

"The constant interaction between aggressive T cells and inhibiting TREG  keeps the immunological balance of our intestinal mucosa intact," explains Prof. Dr. Jan Buer, work group leader at the Helmholtz Centre for Infection Research. "Many chronic, inflammatory intestinal ailments occur because this balance no longer functions," he says. Buer hopes that a better understanding of the processes involved could open up opportunities to selectively turn immune system responses up or down. "That," he says, "could lead to possible therapies for autoimmune diseases, like Morbus Crohn, but also tumors and infections in which the immune reaction needs to be selectively activated."

 

 

Original article:

Westendorf A.M.,  Fleissner D., Deppenmeier S., Gruber A.D., Bruder D., Hansen W., Liblau R., Buer J. (2005). Autoimmune mediated intestinal inflammation – impact and regulation of antigen specific CD8+ T cells. Gastroenterology 131(2):510-24

 

 

Background: New name for the GBF

As of July 18, 2006, the German Research Center for Biotechnology (GBF) in Braunschweig has been operating under a new name: The Helmholtz Centre for Infection Research. The new name is designed to underscore the main thrust of the research conducted at the institute and to more clearly define the institute's membership in the Helmholtz Association, Germany's largest scientific organization.

 

Caption:

Intestinal bacteria at the surface of epithelial cells. Right side: Microvilli of the intestinal mucosa.
Photograph: Helmholtz-hzi/ Kurt Dittmar

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2006-11-17

Better Quality Water – All Across Europe

Helmholtz Centre coordinating EU Drinking Water Research Project

Potable water is our most important nutrient. We drink it every day. That's why it is even more important to know what sort of microorganisms are in the water we drink and what diseases these can cause in humans if they occur in sufficient numbers. Scientists at the Helmholtz Centre for Infection Research in Braunschweig are now coordinating an EU project that is exploring this question. With this "Healthy Water" project, the European Union is aiming to learn more about the quality of its water and apply this knowledge toward improving its drinking water guidelines. The project will run over a period of three years at a cost of € 2.4 million. It is financed by the European Union.

"The drinking water quality in Germany," says project coordinator, Dr. Manfred Höfle, "is outstanding." Unfortunately, this same degree of safe and potable water does not exist everywhere in Europe. That's why one key focus of the project is on high risk water sources and distribution systems. Another problem is that monitoring water resources for pathogen impurities is less than satisfactory. "We currently only determine one particular bacteria count," says Höfle," and that is E. coli. We know virtually nothing about the frequency of other bacteria, viruses, or so-called protozoa, which are single-cell animals."

Helmholtz scientists hope to test and develop further a new kind of chip they are working on with the other nine EU project partners from industry and the research community. The chip is designed to detect microorganisms that have not been empirically catalogued in the past. Dr. Höfle and his colleagues are building on their experience with the so-called "aqua-chip", which has already proved effective in detecting bacterial pathogens.

"What we now want to do is increase the number of pathogens we can detect and make the chip sensitive to viruses," explains Dr. Ingrid Brettar, one of the scientists involved in the project. This requires a great deal of sophistication because for bacteria and protozoa DNA is used as proof. Many viruses, on the other hand, store their genetic information on RNA molecules. "The chip," emphasizes Brettar, "must therefore recognize both DNA and RNA."

The new chip will be able to detect previously ignored germs in our drinking water. This ability will open up new opportunities for protecting humans from water-borne infectious diseases. "We suspect that contaminated water causes more illnesses than generally believed," says Dr. Höfle. But to find out which infectious diseases in Europe are induced by unhygienic water, the consortium of scientists involved in the EU project is not banking on the new chip alone. "We also intend to conduct a broad epidemiological study, sending questionnaires to doctors in specific parts of Europe to identify factors that could suggest a correlation between infections and unclean drinking water," Höfle explains. "So far, we do not have this kind of structured data in Europe," he notes. "We think this will give us some indication which pathogens we should pay particular attention to when developing the chip. In doing so, we hope to make a significant contribution toward improving the quality of drinking water in Europe."

more information about the project 

2007-01-03

Iron Rivets in Cellular Building Blocks

Microorganisms Living in Sulfuric Acid have a Unique Biochemical Machinery

The fact that Ferroplasma acidiphilum, a single-celled organism lacking a protective cell wall, is capable of living in sulfuric acid is already extraordinary. But what really makes the microbe unique is its unusual relationship to iron. Researchers in Braunschweig and Madrid have discovered that Ferroplasma acidiphilum not only extracts energy from iron – it "eats" the metal and leaves rust behind – but also uses it as an essential structure organising element for most of its cellular proteins. This biochemical apparatus differentiates Ferroplasma acidiphilum from all other known organisms. Quite possibly the microorganism has retained a primordial characteristic from the earliest days of evolution. The research findings have now been published in the most recent edition of the scientific journal Nature.

 

"Ferroplasma acidiphilum is a so-called archaebacterium, a microbe that exists in unusual, mostly highly extreme environments," explains Dr. Olga Golyshina from the Helmholtz Centre for Infection Research in Braunschweig, who discovered the germ in pyrite ore a few years ago. Ferroplasma, as the name suggests, lives in acidic iron-rich environments, like drainage streams from abandoned mines. "Because the energy yield from iron oxidation is so minimal, Ferroplasma metabolizes iron-containing rock by the ton, to extract energy for its growth," notes Professor Ken Timmis, the lead scientist for this project at the Helmholtz Centre for Infection Research. "It thereby performs an astounding biogeochemical work," adds Timmis.

 

Together with colleagues in Braunschweig and the CSIC Institute of Catalysis in Madrid, Prof. Timmis studied key components of the cell – the proteins – of Ferroplasma, and made an amazing discovery: "Almost all of the proteins of Ferroplasma acidiphilum contain atoms of iron," says Dr. Peter Golyshin, who works at both the Braunschweig Technical University and Helmholtz Centre. "In all other organisms surveyed, including other archaebacteria, only a minor fraction of the cell’s proteins contain iron." In most instances, the iron atoms in Ferroplasma proteins serve as anchors that hold together the flexible protein chains. The term "iron rivet" was coined for this property.

 

The discovery of this iron rivet-dominated protein machinery of Ferroplasma acidiphilum suggests new ideas about the early stages of evolution. "One current theory on how life began," says Prof. Timmis, "proposes that the first biological molecules would have formed on iron-sulfur, energy-rich surfaces, such as pyrite. Indeed, iron-sulfur mediated catalysis is a feature of some current biochemical reactions. Our results suggest that the first primordial cells may not only have exploited iron in iron-sulfur catalysis, but also as a primitive protein structure organiser. Later, as life form radiated to other habitats containing little iron, evolution will have selected other types of structure organiser". "An exception to the normal iron-limited world is the environment in which Ferroplasma acidiphilum can be found, even today," says Timmis, "where soluble iron is freely available. Perhaps Ferroplasma belongs to a branch of evolution that never left this environment and therefore never needed to replace its iron rivets."

 

Original article:


M. Ferrer, O.V. Golyshina, A. Beloqui, P.N. Golyshin, K. N. Timmis. The cellular machinery of Ferroplasma acidiphilum is iron-protein-dominated. Nature 2007

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2007-01-12

Advanced Training for Young Scientists in Lower Saxony

The Helmholtz International Research School for Infection Biology in Braunschweig and Hanover starts a new PhD program

The goal of the Helmholtz International Research School for Infection Biology  is training top-notch young scientists for cutting-edge biomedical infection research. A PhD program open to young talented early stage researchers from all over the world is scheduled to start in Braunschweig and Hannover this year. Students of medicine and the life sciences may apply for the program until the end of March 2007.

 

Of the 20 participants to be selected by the institutions involved in the program, at least 10 will be from abroad. This challenging program for young academics has been organized by the Helmholtz Centre for Infection Research in Braunschweig, the Hanover Medical School (MHH) and the Foundation of the Hanover Veterinary School (TiHo). The Helmholtz Association, Germany's largest research organization  is  supporting the training program with  1.8 million € over the next six years.

 

Dr. Hansjörg Hauser, spokesman of the Helmholtz International Research School, emphasizes that applicants are expected to bring with them above average qualifications and a willingness to work. In addition to laboratory training and work on their doctoral theses, students will attend a specially tailored program including symposia, lectures, the Helmholtz Summer School and weekend seminars on special topics. Furthermore, students will be given instruction on finance, patent issues and management skills pertinent to a modern scientific career. All course work will be taught in English.

 

Dr. Siegfried Weiss, co-initiator of the Helmholtz International Research School for Infection Biology and a group leader at the Helmholtz Centre for Infection Research, notes that "Today, competent infection research is more important than ever. This is especially apparent in the light of the alarming emergence of diseases such as AIDS, SARS and avian flu." Dr. Weiss points out that many of the molecular connections involved in these diseases are now known but are also very complex. The research methods used to study infections are so specialized, he says, that the curriculum of a conventional university degree program is no longer sufficient.

 

However, the scientific expertise gained by young researchers at institutions like the Helmholtz Centre, TiHo or MHH, are not the sole advantage of such a special training program. "Doctoral candidates meet on a regular basis, they form mutually helpful groups and friendships," Dr. Sabine Kirchhoff, the coordinator of the Helmholtz International Research School for Infection Biology, explains, "and this helps establish a network of good contacts that span the globe, which is very advantageous for any future scientific career."

 

Since 2004, the Helmholtz Centre for Infection Research has been training highly-qualified young infection researchers as part of the EU program "Marie Curie Actions". Twelve doctoral candidates from around the world came to Braunschweig to do research on the molecular interaction of infection processes. Their Ph.D. work will most likely be completed in the course of 2007.

Further information and contact for applications: <link link-intern einen internen link im aktuellen>http://www.helmholtz-hzi.de/?id=1116

 

2007-02-09

Hotline to the Brain

Scientists find Connection between Nerve Cells and Immune System in Mice

A direct connection exists between the brain and the immune system – at least in mice. Scientists at the Helmholtz Centre for Infection Research in Braunschweig conducted a comprehensive study of mice intestine and the surrounding blood and lymph vessels using special microscopy and marking techniques. What they found: numerous immune cells imbedded in the tissue around the intestine are joined to nerve strands and cells. "We already have many indications that immune defenses are at least partially influenced by the nervous system," explains Helmholtz scientist Dr. Kurt Dittmar. "We have now seen these connections under the microscope." In all probability, says Dittmar, the situation in humans is not all that different to mice. The assumption is that the brain and psyche in mice have an effect on the immune system. "For many infectious diseases and autoimmune ailments," he says, "connections have been observed on a regular clinical basis between the psyche and the severity of an illness."

 

The Helmholtz researchers are not quite ready to speculate on the specific interactions at work. According to Dittmar, not enough is known about how the nervous system regulates immune defenses. "Research into the interactions involved is still in the early stages," he says, "but the cell connections studied could, in the near future, also lead to a better understanding of the paths of some infections, e.g. for prions that induce mad cow disease, which could enter the nervous system through the intestines."

 

Novel coloration methods for tissue

In their research, the scientists used the techniques of histochemical immunology: antibodies that are produced against molecules on a cell surface that only appear on certain tissue types are marked with a specific dye. Different tissues take on a different color under a light microscope. "We have developed this method further," says Helmholtz guest researcher, Bin Ma, from China. "We can now characterize up to seven cell types simultaneously in histological cross-sections and, so far, we have made visible an astounding number of contacts between immune and nerve cells." These include some of the most important immune cell types, such as B-lymphocytes, T-lymphocytes and dendric cells – all of which form connections to the nerves. Furthermore, it has also been discovered that quite a few nerve strands end in lymph glands around the intestines, such as the so-called Peyer's patches, where immune cells gather. Researchers also found indications that immune cells can recognize transmitters, the messenger substances of the nervous system.

 

Original article:

Additional information is available from the original article: B. Ma, R. von Wasiliewski, W. Lindenmaier, K.E.J. Dittmar. Immunohistochemical Study of the Blood and Lymphatic Vasculature and the Innervation of Mouse Gut and Gut-Associated Lymphoid Tissue. Anat. Histol. Embryol. Volume 36, issue 1 (2007).

 

Pictures:

ma_01: Helmholtz scientist Bin Ma. Photograph: Helmholtz-HZI / Hübner

dittmar_01: Dr. Kurt Dittmar. Photograph: Helmholtz-HZI / Hübner

lindenmaier_01: Dr. Werner Lindenmaier. Photograph: Helmholtz-HZI / Hübner

neuroimmun:Tracing the „hotline to the brain“: Helmholtz scientists Dr. Werner Lindenmaier (left), Bin Ma, Dr. Kurt Dittmar (right). Photograph: Helmholtz-HZI / Hübner

Nerven_01, Nerven_02: Making contact: Nerve fibres (red) between immune cells (green, blue). Photograph: Helmholtz-HZI/Dittmar

 

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2007-03-06

Quick Test to Protect Children from Heart Disease

Joint European-Indian project targets deadly streptococci

A streptococcal infection may initially cause  nothing more than a relatively harmless sore throat. It can, however, also lead to potentially fatal disease or lifelong disability. The outcome of a primary streptococcal infection depends on the strain of bacteria involved and frequently on the individual susceptibility of the patient. Scientists are now in the process to develop a test that will allow a quick diagnosis of streptococcal strains with potential to cause serious disease. Researchers are evaluating patient samples from India, where children in particular have a high frequency of exposure to strep-tococcal infections. The research project, known as ASSIST, includes partners from Europe and In-dia and is being coordinated by the Helmholtz Centre for Infection Research in Braunschweig. The European Union is funding the project with € 1.5 million.

 


Experts estimate that every year streptococcal infections occur in around 600 million people. Most of them experience brief throat or larynx infections. Some two million others, however, suffer from po-tentially harmful complications. Among these are so-called invasive illnesses which destroy cells and tissue, as well as rheumatic fever, which often leads to cardiac damage.

 


"Rheumatic heart disease, as a secondary effect of streptococcal infections, progresses very dramati-cally," explains Prof. Singh Chhatwal, departmental director at the Helmholtz Centre and coordinator of the ASSIST project. "It occurs primarily in children and frequently only a cardiovalvular trans-plant can save the child." Of the 15 million children worldwide suffering from rheumatic heart dis-ease, six million alone live in India. "The proper diagnostic methods are often lacking, resulting in inadequate treatment by antibiotics, “says Chhatwal, who was born in India and has first-hand knowledge of the situation there. There are grounds for optimism, however. Less than ten percent of the streptococcal strains are capable of triggering serious complications. "If we had an effective test to quickly diagnose whether a patient is infected with a dangerous strain, then we could concentrate on these cases," notes Chhatwal and points out that because the number of these cases is much lower than the total number of infected cases it would be much easier to introduce proper antibiotic treat-ments in poor countries.


Researchers working on the ASSIST project will be gathering information about the streptococcal strains prevalent in India over the next few years. They will also be examining the congenital dispo-sitions of people that make them more susceptible to dangerous pathogens. When this information is collected and evaluated they hope to develop a quick test for streptococcal infections. One avenue being explored is a process to identify specific surface molecules or genes that appear only in dan-gerous strains. Data will be gathered from patients in the age group most at risk in the most affected region of the world. "The Indian project partners," says Chhatwal," will take and evaluate throat swabs from 25,000 Indian school children."

 

The ASSIST research project


ASSIST is an acronym based on several first letters of the full project name: "Comprehensive approach to un-derstand streptococcal diseases and their sequelae to develop innovative strategies for diagnosis, therapy, pre-vention and control." Project partners, besides the Helmholtz Centre for Infection Research, include the Karo-linska Institut Stockholm (Sweden), the University of St. Andrews (Great Britain) as well as three Indian par-ticipants – the Postgraduate Institute of Medical Education in Chandigarh, the Christian Medical College in Vellore and the All Indian Institute of Medical Sciences in New Delhi. The European Union supports ASSIST as part of its program "Specific measures in support of international cooperation" (INCO).

 

Photographs:

 

Chhatwal_2006_04:

Prof. Singh Chhatwal, leading scientist at the Helmholtz Centre for Infection Research.

Photograph: Helmholtz-HZI

 

Poster_indisch:

Indian poster warning of the potential dangers of a streptococcal infection.

Photograph: Helmholtz-HZI

 

 

Indien_Halsabstrich:

Indian girl attending a medical screening.

Photograph: Helmholtz-HZI

 

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2007-05-08

Fighting Cancer with Salmonella

How the Medical Profession can use Bacteria

Disease-causing bacteria can help in the fight against cancer. This may sound a little far-fetched at first, but in future bacteria could form the basis for innovative tumor therapies. Researchers at the Helmholtz Centre for Infection Research in Braunschweig have succeeded in planting "remote-controlled" salmonella in the tumors of cancer-bearing mice. The genetically modified microbes can produce substances on command. "Perhaps at some point," hopes Helmholtz scientist Dr. Holger Loessner, "we will be able to make these bacteria secrete cell toxins precisely where they are needed: in the middle of cancerous tissue."

 

Dr. Loessner's hopes are based on a curious phenomenon that researchers have known about since the mid-19th century. When tumor patients encounter a bacterial infection, frequently tumors are colonized by the bacteria and provide a niche for their multiplication. What exactly triggers this behavior is not well understood. "We suspect that the dead tissue inside the tumor provides these bacteria with a protective and nutrient-rich environment, and therefore, attracts them," explains Dr. Siegfried Weiss, head of the project group "Molecular Immunity" at the Helmholtz Centre for Infection Research. "Tumor interiors," he adds, "are low in oxygen, conditions under which many types of bacteria thrive."

 

For Weiss, Loessner and their colleagues, more important than the basic principles are the possibilities this phenomenon opens up. The rush by bacteria to colonize tumors suggests this behavior could be used for human benefit. Weiss and Loessner have now shown that this is essentially feasible. For the first time, they inserted in bacteria of the genus Salmonella typhimurium, a gene cluster which can be "switched on" by administration of a simple sugar molecule called L-arabinose. Applying L-arabinose, after the salmonella bacteria have infected mice and migrated to the cancerous tissue, activates these genes. Thus far, Weiss and Loessner used genes that encode light emitting proteins. If the mice are given a dose of the sugar, bacteria that have colonized the tumor fluoresce, such that the location and size of the tumor can be analyzed. Theoretically, instead of emitting light, the bacteria in future could be triggered to produce and deliver cancer-fighting medication inside the tumor.

 

Alternatively, they could also deliver immune-stimulating substances that would mark the tumor for the body's own immune-defense mechanisms and induce a salutary immune response. "For medical purposes, of course," notes Dr. Loessner, "we would not use dangerous pathogens, but rather mutant strains that are harmless to humans."

 

"Until now, people have viewed salmonella as a threat to their health," says project leader Weiss, "so there would be a certain charm in using such bacteria for treatment of such a terrible disease as cancer."

 

Source Material

 

Original article: H. Loessner, A. Endmann, S. Leschner, K. Westphal, M. Rohde, T. Miloud, G. Hämmerling, K. Neuhaus, S. Weiss: Remote control of tumour-targeted Salmonella enterica serovar Typhomurium by the use of L-arabinose as inducer of bacterial gene expression in vivo. Cellular Microbiology 2007 (doi: 10.1111/j.1462-5822.2007.00890.x). The paper can be viewed online at: www.blackwell-synergy.com/toc/cmi/0/0

 

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2007-06-01

Why Mice Succumb to Human Diseases

Evolution in the Lab: Researchers of the Helmholtz-Association reveal how Pathogens adapt to new Victims

The bacterium Listeria monocytogenes is able to infect humans causing diarrhea, meningitis, still birth or miscarriage. Mice, by contrast, are largely immune. This difference may be traced to the bacterial protein Internalin (or InlA), a molecular key that provides the bacterium with a route of access to cells lining the small intestine. In mice this mechanism is disabled, so that bacteria are unable to cause an infection. This represents a distinct disadvantage for medical research as new treatments cannot be tested using mice. Researchers at the Helmholtz-Centre for Infection Research in Braunschweig, Germany, now demonstrate how a minor modification in InlA enables the bacterium to infect mice.

In nature, bacteria change continually. “Most newly emerging infectious diseases, including the plague in the Middle Ages and the current bird flu, result from animal pathogens suddenly adapting to humans,” says Dr. Wolf-Dieter Schubert, group leader at the Helmholtz-Centre for Infection Research. “We refer to this as a change in host specificity. The adaptation of the influenza virus H5N1 from birds to humans has, in this context, not only been a major concern for the general public, but has also resulted in appreciable economic losses.” This is also true for HIV, the causative agent of AIDS, which was able to bridge the gap between apes and humans.

We have simulated this breaching of the host barrier in the lab – but in the opposite direction, namely from humans to animals” describes PhD-student Thomas Wollert. “This was possible because we understand the three-dimensional structure of InlA in atomic detail.

During listerial infections, InlA allows the bacteria adhere to the surface of the intestinal lining. This is possible because InlA recognizes its receptor E-cadherin located on the corresponding cells with high precision. E-cadherin is also present in the intestine of mice, but differs from its human counterpart in small but crucial sites.

“As a result, InlA recognizes human E-cadherin but not the variant found in mice ” says Thomas Wollert. “If we only replace two of 764 amino acid building blocks of InlA, it binds more tightly to human E-cadherin but, more significantly, it additionally recognizes the murine version.” Similar substitutions of such building blocks happens spontaneously in nature. “If we understand the principles governing the host specificity of pathogens,” declares Dr. Schubert, “we should  be able to predict in advance, which pathogens are particularly likely to adapt to humans”.

 

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2007-08-07

Dumping Useless Genes

Helmholtz researchers develop programmable mini-bacteria

Bacteria are genetically equipped with tremendous variability. As a result, these microorganisms are extremely flexible in their responses to the surrounding environment. From the standpoint of biotechnology, many bacterial genes are useful, while others are not. Researchers at the Helmholtz Centre for Infection Research in Braunschweig have now launched a project to reduce the bacterial genome of Pseudomonas putida to its essentials and, at the same time, insert additional genetic circuits.

Equipped with this new genetic makeup, P. putida would turn aromatic chlorine compounds – annular structures with one or more chlorine atoms – into more valuable pharmaceutical compounds.

The project, called "Probactys" for "Programmable Bacterial Catalysts", will operate over three years and is supported by a European Union grant of 1.9 million euros.

The genetic programming undertaken by the Helmholtz researchers is aimed at forcing the bacteria to work together in a coordinated and synchronized fashion. At the same time, undesirable metabolic by-products would be blocked and biocatalysis would proceed at low temperatures. "Ideally, the bacteria with the mini-genome would also be receptive to a targeted, accelerated evolution," says Dr. Vitor Martins dos Santos, a systems biologist at the Helmholtz Centre and the project's coordinator. "That would make it possible to continuously improve the metabolic circuitry." "In turn, these cells could then take over very effective and special functions for biotechnological, ecological or medical tasks," he says.

The Braunschweig scientists are working with colleagues from Spain, France, Britain, the Netherlands and China. The "Probactys" project is more than just typical laboratory research, or what scientists refer to as wet lab work. The researchers also have to develop cellular models on the computer, the so-called dry lab. This is an enormous task that requires international partners to ensure that the goals of the project are met.

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2007-10-30

A new Knowledge Website for Infection Research

„infection-research.de“ covers the latest research developments

From antibiotic resistance to zoonotic diseases, from the developing to the developed world, infectious disease remains a profound health threat. Stay abreast of the latest research in infection at the new knowledge website „Infection Research-News and Perspectives“ (www.infection-research.de) Researchers at the Helmholtz Centre for Infection Research (HZI), in Braunschweig, Germany, created the site with support from the German Association of Science Charities (Stifterverband für die Deutsche Wissenschaft).

„Infection research is experiencing something of a rebirth“, explains HZI’s Klaus Schughart as his motivation starting the website. „Infectious diseases that we had once thought we had defeated now claim many deaths. And previously unknown invaders appear and spread rapidly throughout the world.” As a consequence at least 17 million people die annually because of an infectious disease. 

New findings in infection research raise hopes of slowing the growth of infectious disease, but as the field grows, scientists must grapple with a flood of information and new controversies. “`Infection Research - News and Perspectives´ aims to give a comprehensive overview of current developments in the field, thus providing an orientation in a fast progressing research field. It will also provide scientist of other disciplines as well as the interested public with insights about facts, activities and the science behind controversies.” Schughart says.

Weekly ´Infection Research´ includes in the “News Section” short summaries of important recent papers and their links to the original paper. In the “Perspective Section”, a new article each month will address a particular research question with facts and background information and explain controversial issues. “Perspectives” will also occasionally address policy issues that will influence which research questions scientists choose to tackle. The “Events” Section informs scientist about upcoming meetings, workshops or conferences. Behind the caption “Who is Who” is a map and a list of the leading infection research institutes in Germany. Future developments include profiles of established scientists who have influenced infection research as well as young scientists at the beginning of productive careers.

www.infection-research.de

2007-11-19

HZI Molecule Transformed into a Cancer Medicine in the United States

Balling: Colossal Success for Biomedical Research in Germany

The pharmaceutical company Bristol-Myers Squibb (BMS) recently obtained approval in the American market for IXEMPRA, a semi-synthetic analog of epothilone B, for the treatment of patients with metastatic breast cancer resistant or refractory to anthracyclines, taxanes, and capecitabine.  The epothilones were originally discovered and researched by scientists at the Helmholtz Center for Infection Research in Braunschweig, Germany.  Bristol-Myers Squibb licensed epothilone technology in 1997 from the Helmholtz Center.  Physicians in the United States will be able to immediately use IXEMPRA, the semi-synthetic epitholone B analog, to treat patients.  Pharmaceutical experts think Ixempra has a great potential as a breast cancer medicine – and later for other types of cancer.  It is anticipated for European licensing in the second half of 2008.  

The team of scientists with the chemist Prof. Gerhard Höfle and the biologist Prof. Hans Reichenbach at the former Society for Biotechnological Research (now under the name of the Helmholtz Center for Infection Research) discovered epothilones as early as in the 80’s. This new class of biologically active natural substances comes from the myxobacteria living in the soil. Epothilones act on what are known as microtubuli in body cells. The microscopically tiny tubes distribute the chromosomes (the media of genetic information) to the daughter cells during cell division. When epothilones come into the cell, they block the microtubuli and the cells cannot divide. Then they die off and are decomposed. Since cancer cells divide particularly frequently, they react very sensitively to epothilone. The result is a deceleration in tumor growth so that tumors shrink and disappear.

The first step in the process of development was the observation of the microbiologist Dr. Klaus Gerth from Reichenbach’s team that a special strain of a type of myxobacteria produces an interesting substance that can kill off living cells. Dr. Norbert Bedorf from Höfle’s natural substance chemistry department produced this substance in pure form for the first time and resolved its chemical structure. That was when epothilone entered the stage of pharmaceutical research.

Then, there followed more years of intensive research because they not only had to enhance the chemical structure, but also improve epothilone production. This is the reason why the myxobacteria were genetically modified to produce new bacteria that could generate sufficient quantities of the epothilones for potential cancer agent. Secondly, the scientists had to create the best conditions for life in bioreactors for the high-performance bacteria bred in this fashion. Finally, this production process was used as a basis for manufacturing the medicine. Bristol-Myers Squibb then developed a semi-synthethic version of epothilone B and conducted the necessary preclinical studies and later global clinical trials with patients in order to apply for a license.

There was great satisfaction with these findings, as Prof. Dr. Rudi Balling, the scientific director of the Helmholtz Center, expressed: “Epothilone proves that public biomedical research in Germany is world class and it can come up with answers to the urgent health problems of humanity. It was the Helmholtz Society that combined high-profile pure research with the perspective of industrial applications.” But, as the success story of epothilone shows, you need a lot of patience.

And that, along with scientific creativity, was Höfle’s and Reichenbach’s key to success. “We are extremely proud of the role of our co-workers in helping to develop this new class of cancer therapy and harvesting the fruits of 30 years of biological and chemical research work.”

2008-01-09

Molecular Attachments Determine Mortality of Cancer Cells

Researchers in the USA and Braunschweig show how these substances work

A highly promising molecular constellation, discovered in the field of pharmaceutical cancer research, is now better understood in terms of its efficacy, thanks to years of laboratory testing. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig have determined the biological activity of the tubulysin molecule. Tubulysin is one of the most powerful cell division inhibitors known to science. Abnormally high, pathological cell division is what makes cancer so dangerous. The new findings are a major step forward in the pharmaceutical development of this important substance.One of the problems with highly poisonous, so-called cytotoxic, substances, like tubulysin, is that, initially at least, a pharmaceutical application would seem out of the question. The substance inhibits the growth of all human cells, not just degenerated, cancerous cells. "From the clinical perspective, this problem is expressed in severe side effects," explains Dr. Florenz Sasse, a biologist at the Helmholtz Institute. These can include alopecia because the substance also attacks the skin cells responsible for hair growth, or, changes in the blood count, leading to an absence of phagocytes, making patients more susceptible to subsequent infections. Problems like these can only be avoided if researchers find a way to alter the substance at the molecular level so that it targets tumor cells exclusively. In the case of tubulysin, chemists in the United States, in conjunction with Florenz Sasse, have made the crucial contribution. They have jointly been able to illustrate just where "tinkering" on the molecule can alter its design and synthesis properties."Tubulysin is a difficult molecule in every respect," notes Dr. Sasse. "It's formed by soil bacteria as a metabolic by-product. We discovered tubulysin in 1994, but because it's a by-product it's difficult to produce in significant amounts." "What's more," she says, "the molecule has been optimized for its function by the bacteria over a long period of evolution. That means for us that individual molecular components cannot be easily varied. If we alter the structure, we lose the potency."However, after a U.S. research group in 2006 managed to reproduce tubulysin synthetically in a test tube, it became possible for scientists to study which parts of the molecule were important for its biological activity. It is now feasible to alter specific areas of the molecule without diminishing its potency, while, at the same time, improving its cancer-fighting qualities. It can now also be attached to other substances, which transport it directly to a tumor growth. "This way, explains Sasse, "we can regulate the toxicity of tubulysin.""There is, however, a long road of development ahead of us before a targeted cancer therapy without side effects is achieved," says Dr. Sasse.Original Article:Andrew W. Patterson, Hillary M. Peltier, Florenz Sasse and Jonathan A. Ellmann (2007): Designs, Synthesis and Biological Properties of Highly Potent Tu 1 bulysin D Analogues. Chem. Eur. J. 2007, 13, 9543-9541

Pictures: Cancer cells withour (download 1) and with (download 2) Tubulysin treatment. blue: Nucleus, green: Cytoskeleton. Photographer: Florenz Sasse

2008-01-28

Tracking Down the AIDS Pathogen

International Aids Researchers to meet at HZI

Noted international experts will be gathering at the Helmholtz Centre for Infection Research (HZI) on January 31, 2008, to discuss the current state of AIDS research. In addition to scientists from Germany and Europe, experts from Israel and the United States will be explaining what makes the HI-virus (HIV) so special, what therapies for HIV infection exist and what progress is being made toward the development of an HIV vaccine. The "'Day on AIDS" is slated to begin at 11 a.m. at the HZI Forum and will end around 6 p.m.

 

Infectious diseases, in general, are responsible for the greatest number of fatalities worldwide, and sadly, HIV/AIDS is one of the leaders on this list. Since the discovery of HIV in 1980, more than 25 million people have died of AIDS. Nearly twice that number is infected with the virus today. Africa, in particular, with infection rates of up to 30 percent of the population, is faced with an enormous social problem.  There is still no cure for AIDS and there is no protective vaccine against HIV infection. On the contrary, HIV is still a major challenge for researchers due to its transformative characteristics.

 

Among the lecturers invited to the HZI "Day on AIDS" is the American researcher, Dr. Ruth M. Ruprecht, from Boston. Dr. Ruprecht has earned many honors and awards in the past for her contributions to AIDS research. Dr. Monika Gröne, from the University of Erlangen, will explain where the AIDS pathogen comes from and where HIV/AIDS research is headed in the future. Besides her research activities, Dr. Gröne is also the editor of Retrovirus Bulletin, which appears regularly on the AIDS website www.HIV.net. Other experts will be lecturing on the structure of HI viruses, the reproductive cycles of the virus in the human body and will discuss protective measures against the spread of HIV/AIDS.

 

We would like to invite you to join us and the international experts for this in-depth one-day symposium to examine and discuss the many sides of AIDS research. All lectures will be conducted in English. The symposium is open to all those who are interested in AIDS research, but we ask that prospective participants register free-of-charge with Dr. Sabine Kirchhoff so that we have an overview of attendance. Her eMail address is: school@helmholtz-hzi.de. The entire program for the symposium can be found at: www.helmholtz-hzi.de/de/forschung/veranstaltungen.

 

The "Day on AIDS" is sponsored by the international Ph.D. program "MIDITRAIN", Helmholtz International Research for Infection Biology (HIRSIB) at HZI, the Hanover Medical School and the Veterinary Foundation/Hanover University. This symposium is the sixth in a series of lectures at HZI whereby internationally-recognized experts discuss key issues in the field of infection research.

2008-02-13

Metabolism, Maths, Medicine: If Bacteria Were Calculable

For the first time, researchers at the Helmholtz Centre for Infection Research (HZI) have produced a comprehensive model of the metabolic processes of the bacterium Pseudomonas aeruginosa. With this, the basis is created for the development of possible new therapy concepts to counteract this infectious germ. The work of the Braunschweig-based researchers also provides an indication of the direction that modern biomedicine is taking: "Today, we increasingly regard cells as an integrated, biological system," says Project Leader Dr. Vítor Martins dos Santos. "With the aid of mathematical models we are now able to partially predict the behaviour of the system and then use simulations to develop new therapy concepts."

Pseudomonas aeruginosa lives almost everywhere. In water, in the soil, on and in us, and in hospitals. The microbe is especially problematic here, as it can attack and render ill patients with immune deficiency in particular. "Bacteria that exist everywhere naturally have a highly variable metabolism, which makes them extremely flexible," says Martins dos Santos. The talk is of a metabolic convertibility. In the case of Pseudomonas this is based upon a genome that is very large for bacteria. Martins dos Santos: "This means that the bacterium is very robust, versatile and reproduces quickly."

The genome of the Pseudomonas strain PAO1 was already completely sequenced in 2000. However, mere knowledge of the precise sequence of the DNA constituents in genetic material does not make germs truly susceptible to newly synthesised antibiotics or other therapeutic approaches. Genes supply the basis for the construction plans for a cell but only make a limited statement with regard to its biological implementation. "We need to know what individual triggers there are for genetic activity and whether their products such as certain enzymes have an effect in cell metabolism. And we need to know this for each time point and each position of the metabolism," states Martins dos Santos. Consequently, he does not only asks what role an enzyme plays in cell metabolism, he really wants to know how it embedded in a the whole metabolic network and whether he can discover it in the rhythm of the cell cycle - he quantifies.

Vítor Martins dos Santos and his team, together with collaborators at the University of Virginia, therefore investigated which functions and reactions can be directly or indirectly influenced by an enzyme or other genetic products. When the HZI researchers had discovered this for all genetic products, they depicted the processes in the form of a network. This is known as a so-called genome-based, metabolic network.

"Thus, we represented the data of a large bacterial genome in the form of a metabolic network," summarises the researcher. "Now we are able to partially forecast what happens when we interfere with the metabolism of Pseudomonas here or there." These simulations should provide references for medicinal interventions, which are often scarce, in particular with regard to infections. "Research has been carried out into cells and germs for over 330 years and yet they are still a 'black box', with no-one really certain what is happening inside," says Martins dos Santos, inferring that system-biological approaches such as these will now be able to make visible what is actually going on inside the cells.

Publication:
MA Oberhardt et al (2008): Genome-scale metabolic network analysis of the opportunistic pathogen Pseudomonas aeruginose PAO1. J. Bacteriol: JB.01583-07v1.

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2008-05-20

Scientific accolade for HZI scientist

Kenneth Timmis awarded UK's highest scientific honor

Prof Kenneth TimmisThe microbiologist Prof. Ken Timmis, Head of the Department of Environmental Microbiology, Helmholtz Centre for Infection Research has just been awarded the highest scientific accolade in Britain. He has just been elected Fellow of the Royal Society, Britain's most venerable scientific and philosophical academy.

Timmis is distinguished for his early contributions to understanding plasmid replication and, especially, for a career-long string of 'firsts' in metabolic pathway engineering. He discovered the pervasive 'minimal replicon' concept for bacterial plasmids, and the paradigm of negative control of plasmid copy number. He cloned and characterised entire bacterial metabolic pathways for the first time, isolated novel regulators of gene expression, and designed novel catabolic pathways from first principles, notably for bioremediation of environmental pollutants. He discovered complex microbe-clay mineral associations in the soil and used a microbial biofilm community to develop a prize-winning strategy for removing mercury from waste streams.

With his election he is now a member of a select scientific community whose members include Stephen Hawking, Tim Berners Lee, Paul Nurse and John Sulston.

This honor, though individual, is of course a recognition of the scientific advances resulting from the collective efforts of all the members of his groups in Berlin, Geneva and Braunschweig. "I therefore take great pleasure in the fact that my colleagues and friends over the years, who have shared with me their intellectual excitement, scientific careers and personal development, have had their successes publicly acknowledged in this manner. It is also a recognition of the excellence of the institutes in which my group has worked over the years, in particular the HZI, which has been home to it for 20 years."

Link zur Royal Society:
http://royalsociety.org/publication.asp?tip=1&id=7696

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2008-06-02

Six Nobel Prize Winners at International Congress of Genetics

Congress Chairman Balling: Olympic Games of Science in Germany

FahnenFahnenFor the first time in 81 years the International Congress of Genetics takes place in Germany again. From July 12th through 17th 2008, six Nobel Prize winners get together with more than 2000 scientists in Berlin to discuss the latest findings in genetics and genome analysis. The congress, which takes place for the 20th time, was last hosted by Germany in 1927, the venue also being Berlin. Congress Chairman is Prof. Rudi Balling, Scientific Director of the Helmholtz Centre for Infection Research in Braunschweig. To him, the 20th ICG in Berlin stresses the high international reputation of genetic sciences in Germany. “We are as happy as if we had brought the Olympic games into the country”, says Balling.

The congress topics include all relevant genetic fields. Stem cell research, the genetics of cancer, applied plant genetics, and new, futuristic topics like synthetic biology will attract the media’s attention. More than 280 renowned speakers, 10 plenary sessions, 54 symposia, and 1400 scientific posters offer insight into the diversity of current genetic research and science. Aside from the role genetic engineering might play in fighting hunger, legal and ethical aspects of genetic research will also be discussed. The history of the genetic field itself will be the topic of one symposium. The congress is hosted by the Deutsche Gesellschaft für Genetik (GfG; German Genetics Society).

The “Who’s Who of Genetics” in Berlin
The attending Nobel Prize winners Prof. Mario R. Capecchi and Prof. Oliver Smithies have been honored for their achievements in 2007, Prof. Richard Axel in 2004. Prof. Christiane Nüsslein-Volhard and Prof. Eric F. Wieschaus received the Nobel Prize in 1995, and Prof. Phillip A. Sharp in 1993. Capecchi and Smithies received the Nobel Prize for “Physiology or Medicine” in recognition of their research which contributed significantly to the development of one of the most important model organisms in science, the so called “knock-out-mouse”. The term “knock-out” indicates that it is possible to turn off single targeted genes in such mice. Prof. Christiane Nüsslein-Volhard from Tübingen received the highest scientific award together with Eric F. Wieschaus for groundbreaking findings in the genetic control of early embryonic development. Richard Axel has been honored for his contributions to the understanding of the sense of smell, and Phillip A. Sharp received the award for the discovery of so called “mosaic genes”, in which the genetic information for the formation of proteins is interrupted by other information units (introns).

75th Anniversary of the Nazi Eugenics Law Prompts a Statement
On the 14th of July, the topic “eugenics” will be part of the congress program. At 12:30pm, Prof. Andre Reis as President of the German Society of Human Genetics and Prof. Wolfram Henn, president of the society’s ethics committee, will present a statement of German human geneticists on the responsibilities for the history of their field. This will take place on the occasion of the 75th anniversary of the enactment of the “law to prevent hereditary diseased offspring”, which was implemented on the 14th of July in 1933, and which gave grounds for the inhuman, forced sterilizations and the euthanasia program. The German Society for Human Genetics comments on the scientists involved then, and takes a stand regarding the current position of German genetics. Afterwards, Mr. Reis and Mr. Henn, as well as Prof. Alfred Nordheim (GfGPresident and co-signer of the statement) and the Canadian expert for health care law, Prof. Bartha Maria Knoppers, will be available for questioning.

Preliminary ICG-Press-Program
12th of July, 3pm, ICC Berlin, room 44: Kick-off-Press conference with the Nobel Prize winners Prof. Mario R. Capecchi, Prof. Oliver Smithies, and Prof. Christiane Nüsslein-Volhard, the Secretary General of the European Research Council, Prof. Ernst- Ludwig Winnacker and the executive board of the congress.
14th – 16th of July, 12:30pm each day, ICC Berlin, room 44: “Topic Talks” on eugenics (July 14), stem cell research (July 15), disease genetics (July 16)

More information is available at: http://www.geneticsberlin2008.com

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2008-06-25

Purple extremist thrives under inhospitable conditions

HZI scientists discovers new protein that repairs DNA under extreme conditions

 Bild: Olga Golyshina (li.) und Peter Golyshin mit ihrem purpurroten Untersuchungsobjekt Ferroplasma acidiphilumBild: Olga Golyshina (li.) und Peter Golyshin mit ihrem purpurroten Untersuchungsobjekt Ferroplasma acidiphilumMild environmental conditions are a prerequisite for life. Strong acids or dissolved metallic salts in high concentrations are detrimental to both humans and to simpler life forms, such as bacteria. Such conditions destroy proteins, ensuring that all biological functions in the cells come to a standstill. So what do we find at the limits of hostile conditions where we still find life? Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig (Germany) have joined up with colleagues from Spain and Great Britain to identify an enzyme that requires acids and dissolved metals in order to function. The team describes its findings regarding the extreme protein of the archaebacterium Ferroplasma acidiphilum in the latest online edition of the renowned US research journal PNAS.

HZI scientist Dr. Olga Golyshina discovered Ferroplasma ten years ago and has been endeavouring to unlock its secrets ever since. "This organism is ideally adapted to extremely hostile environments. It likes to live in highly acidic solutions containing toxic heavy metals. It is unable to exist at all under normal conditions," she says, describing her research object. "We recently noted that Ferroplasma is unique in the world of living organisms, as it contains iron in high concentrations. Now we aim to discover how its proteins function under such extreme conditions."

For this purpose the team has selected a so-called DNA ligase. Enzymes of this type play a central role in important metabolic processes such as the duplication of genetic material in dividing cells and the repair of genetic damage. All DNA ligases investigated so far, including the DNA ligases of the so-called extremophile microorganisms that live in particularly inhospitable habitats which are either acidic, alkaline, hot or cold, , require mild environmental conditions. "The Ferroplasma DNA ligase is unique," states Olga Golyshina: "It actually requires extremely acidic conditions to work."

Iron gives the protein a purple colour

But this is not the only thing that scientists find surprising about this survival expert: "All of the DNA ligases studied so far do not contain iron, but require magnesium or potassium to function. Extraordinarily, the DNA ligase of Ferroplasma contains iron and does not need either magnesium or potassium. The iron is essential: removal results in loss of activity and, interestingly, its wonderful purple coloration."However, the colour is less fascinating than the fact that Ferroplasma does not die as a result of the ordinarily toxic high concentration of iron in its cells which would severely damage genetic material in other cells, triggering mutations.

"The fact that an enzyme contains metal ions that damage DNA for the repair of DNA seems contradictory," says project partner Prof. Peter Golyshin, who works at the HZI and Bangor University in Wales (GB). He suspects that the Ferroplasma genus occupied its ecological niche early in evolution. At that time the earth was very inhospitable; acids and metals in soluble form were everywhere. Peter Golyshin: "Maybe the ancestors of Ferroplasma integrated these substances into their metabolism. And afterwards  they never left its environment, even as this became increasingly scarce on earth."

Prof. Ken Timmis, Head of the Environmental Microbiology Group at HZI, is considering the future uses of the findings of the team: "Enzymes are required for many biotechnological applications. The chemical conditions under which these processes occur are often rather hostile. Enzymes from Ferroplasma, such as DNA ligase, clearly are ideally suited for processes that require hostile conditions, so this microbe may represent a rich source of biological catalysts not thus far obtainable from any other source”. Timmis also considers applications in the field of medicine a possibility: "The possibility of DNA repair under acidic conditions may ultimately provide a new treatment option for disease conditions characterized by over-acidification of cells that favour the formation of tumours."

Title of original publication:
Manuel Ferrer, Olga V. Golyshina, Ana Beloqui, Lars H. Böttger, José M. Andreu, Julio Polaina, Antonio L. De Lacey, Alfred X. Trautwein, Kenneth N. Timmis, and Peter N. Golyshin: A purple acidophilic di-ferric DNA ligase from Ferroplasma. PNAS published June 24, 2008, 10.1073/pnas.0800071105 (Biochemistry)

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2008-07-08

Argyrin: natural substance raises hope for new cancer therapies

Scientists at HZI, MHH and LUH publish previously-unknown chemical mechanism

Ronald Frank  Nisar Malek  Markus KalesseThe effective treatment of many forms of cancer continues to pose a major problem for medicine. Many tumours fail to respond to standard forms of chemotherapy or become resistant to the medication. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, the Hannover Medical School (MHH) and Leibniz-Universität (LUH) in Hanover have now discovered a chemical mechanism with which a natural substance - argyrin - destroys tumours. Today, the researchers publish their findings in the renowned scientific journal "CancerCell".

The basis for this breakthrough was an observation made by the MHH scientist Prof. Nisar Malek: he had been studying the role of a certain protein - a so-called cyclin-kinase inhibitor - in the development of cancer. In the process, Malek noted that mice in which the breakdown of the kinase inhibitor was suppressed by genetic change have a significantly lower risk of suffering from intestinal cancer. "I needed a substance that would prevent the breakdown of the protein that I was investigating in the cancer cells," says Nisar Malek: "This molecule, in all likelihood, would make a good anti-cancer agent."

Nisar Malek approached Dr. Ronald Frank, a chemist at HZI, with his considerations. Ronald Frank has established extensive collections of chemical substances at the HZI that can be tested for their biological activity in a fast, automated procedure. The two agreed to develop a special cell line in which the quantity of the cyclin kinase inhibitor can be measured using simple optical methods. Ronald Frank: "We adapted this cell based assay system to allow automated screening of large numbers of different chemical substances.”

“Myxobacteria provide another potential cancer medicine

Malek and Frank found what they were looking for in a collection of natural substances which had originally been isolated from microorganisms which live in soil – the so called Myxobacteria. Myxobacteria have proven to be a treasure trove of potential medicines, also being used in the production of epothilone, an active agent identified at the HZI. This drug has been approved as a cancer medicine in the USA last year. "The myxobacterial agent for our purposes is argyrin," says Ronald Frank.

With this knowledge, Ronald Frank and Nisar Malek joined up with the chemist Prof. Markus Kalesse of the LUH to launch an extensive research programme to discover how argyrin can be produced chemically and how it functions. In the process they stumbled upon a completely new mechanism, which was subsequently revealed in a publication in the non plus ultra of oncology journals, "CancerCell". "Argyrin blocks the molecular machinery of the cell which breakdowns proteins that are no longer required," explains Malek, "and thereby naturally also prevents the breakdown of the kinase inhibitor in question, the lack of which triggers cancer."

The research team has already conducted detailed studies of the effects of argyrin on mice: "When we treat animals with cancer with argyrin," says Nisar Malek, "the tumour ceases growing, it decreases by up to 50 percent and it begins to breakdown internally." Scarcely any side effects have been noted. Although the findings published in CancerCell are viewed by the scientists as an important result, it is merely the first step of a longer journey: "Research into argyrin continues at a fast pace," says Markus Kalesse: "We are already altering the argyrin molecule in all details and looking to see if it is possible to improve its performance further. Our goal is to submit such an optimised structure for clinical testing in the near future."

Title of the Original Publication:
Irina Nickeleit, Steffen Zender, Florenz Sasse, Robert Geffers, Gudrun Brandes, Inga Sörensen, Heinrich Steinmetz, Stefan Kubicka, Teresa Carlomagno, Dirk Menche, Ines Gütgemann, Jan Buer, Achim Gossler, Michael P. Manns, Markus Kalesse, Ronald Frank, and Nisar P. Malek: Argyrin A Reveals a Critical Role for the Tumor Suppressor Protein p27kip1 in Mediating Antitumor Activities in Response to Proteasome Inhibition; Cancer Cell 2008 14: 23-35.

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2008-07-22

Biofilms use chemical weapons

Researcher at the Helmholtz Centre for Infection Research discovers defence strategies used by biofilm bacteria

 image Matz et al 2004Bacteria rarely come as loners; more often they grow in crowds and squat on surfaces where they form a community together. These so-called biofilms develop on any surface that bacteria can attach themselves to. The dilemma we face is that neither disinfectants and antibiotics, nor phagocytes and our immune system can destroy these biofilms. This is a particular problem in hospitals if these bacteria form a community on a catheter or implant where they could potentially cause a serious infection. Scientists at the Helmholtz Centre for Infection Research in Braunschweig have now identified one of the fundamental mechanisms used by the bacteria in biofilms to protect themselves against the attacking phagocytes. The scientists are now publishing their findings in the renowned specialist publication PLoS ONE, together with colleagues from Australia, Great Britain and the USA – the discovery being that biofilm bacteria use chemical weapons to defend themselves.

Until now, scientists have been unable to understand the root of the biofilm problem – the inability of phagocytes to destroy these biofilms. Dr. Carsten Matz decided to investigate this problem. As a model for his investigation, this Braunschweig-based researcher decided to look at marine bacteria. They face constant threats in their habitat from environmental phagocytes, the amoebae, which behave in a similar way in the sea as the immune cells in our body: they seek out and feed on the bacteria. So long as bacteria are swimming freely and separately in the water, they are easy pickings for these predators. However, if they become attached to a surface and socialize with other bacteria, the amoebae can no longer successfully attack them. “The surprising thing was that the amoebae attacking the biofilms were de-activated or even killed. The bacteria are clearly not just building a fortress, they are also fighting back,” says Carsten Matz.

The bacteria utilise chemical weapons to achieve this. A widespread and highly effective molecule used by marine bacteria is the pigment violacein. Once the defence system is ready, the biofilm shimmers a soft purple colour. If the attackers consume just a single cell of the biofilm – and the pigment they contain – this paralyses the attackers momentarily and the violacein triggers a suicide mechanism in the amoebae.

“I feel that these results could offer a change of perspective,” says Carsten Matz. “Biofilms may no longer be seen just as a problem; they may also be a source of new bioactive agents. When organized in biofilms, bacteria produce highly effective substances which individual bacteria alone cannot produce.” And the scientists hope to use these molecules to combat a specific group of pathogens: Human parasites that cause devastating infections such as sleeping illness and malaria. Amoeba are ancient relatives of these pathogens and thus biofilm-derived weapons may provide an excellent basis for the design of new parasiticidal drugs.

Original publication: Carsten Matz, Jeremy S. Webb, Peter J. Schupp, Shui Phang, Anahit Penesyan, Suhelen Egan, Peter D. Steinberg, Staffan Kjelleberg: Marine biofilm bacteria evade eukaryotic predation by targeted chemical defense. PLoS ONE published July 23, 2008, doi/pone.0002744

 

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2008-09-11

New from Old

Novel tuberculosis vaccine in Germany in clinical phase

 Tuberkulose_ErregerTuberkulose_ErregerFor the first time in more than 80 years a promising live vaccine against tuberculosis has passed into the clinical phase in Germany: Since Monday of this week the new vaccine, which goes by the designation "VPM1002", has begun safety testing on volunteers in a Phase I clinical trial in Neuss, Germany. It is based on a highly safe vaccine that was introduced in 1921. However, the vaccine has been genetically developed to an extent where it is significantly more effective at preventing infection with tuberculosis bacteria than its predecessor. So far, VPM1002 has proved to be extremely effective and safe in animal models. „ This good protection now has to be proven in humans for the vaccine to be ready for the final approval,” explains the Chief Executive Officer of Vakzine Projekt Management GmbH (VPM), Bernd Eisele.

VPM coordinates application-oriented development of vaccines. The organisation is a public-private partnership established by the Federal Ministry of Education and Research (BMBF) and Helmholtz Centre for Infection Research in 2002. „ We ensure that the outstanding results of basic science are actually used for the good of mankind and make their way into use,” says the Clinical Project Manager Hans von Zepelin. In this, the superb contacts enjoyed by VPM within German science prove a great aid, as the Scientific and Technical Services Manager at the Helmholtz Centre for Infection Research, Rudi Balling, states:  “VPM knows exactly where promising projects can be found. With their assistance we, the researchers, can show that our ideas are helping people to stay healthy.”

With the financial support of the BMBF VPM was able to licence the novel tuberculosis vaccine from the Max Planck Institute for Infection Biology. The scientific foundation was established in this institute by its Founding Director Stefan H.E. Kaufmann. “The new vaccine is based on the most administered live-vaccine worldwide: Bacille Calmette-Guérin (BCG). However, BCG often fails to display effects anymore. We wanted to sharpen the blunted weapon that is BCG once again.”

How this was achieved is described by Leander Grode, at that time a research assistant with Stefan H.E. Kaufmann and now Project Manager at VPM: “The weakened vaccine was genetically modified in such a way to ensure that it is no longer able to hide from the human immune system and even stimulates the body’s own defences now.” For that a gene of a different bacterium, Listeria, was inserted into the vaccine. “Macrophages of the human immune system take up the vaccine immediately. There it ends up in phagosomes”, says Grode. “Due to the genetic modification the bacteria can leave the phagosomes and are then present in the middle of the immune cell – this alarms the rest of the immune system, which is then armed to repel real tuberculosis pathogens.”

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2008-10-17

New antibiotic candidates from Braunschweig

Mode of action of HZI natural products elucidated – substances also act against bacteria that are resistant to antibiotics

 Irschik JansenA group of antibiotic natural products discovered at the Helmholtz Centre for Infection Research (HZI) in Braunschweig points out a new mode of action against pathogenic bacteria. Isolated from myxobacteria, the substances prevent an enzym of the pathogens from being able to translate their genetic material. In this way, the propagation of bacteria – such as tuberculosis pathogens - is inhibited. A working group at Rutgers University in New Jersey (USA) has now joined up with HZI researchers and discovered in detail how these compounds interact with the target in pathogenic bacteria. The novel target is different from the target of known antibiotics such as rifamycin, a standard medication to counteract tuberculosis.

This discovery makes the Braunschweig natural products extremely interesting candidates for a development as antibiotics – especially in view of the fact that the substances also kill bacterial strains that are resistant to antibiotics. Today, the scientists publish their results in the distinguished journal "Cell".

Antibiotics are an essential tool of medicine. We owe the antibiotics that diseases such as plague, cholera or tuberculosis are a thing of the past, at least in the industrialised world.

However, more and more bacteria are becoming resistant to medication. Consequently, doctors are in urgent need of new antibiotics. Their development is a demanding challenge: the drugs should attack the bacteria only but not interact with human cells. Subsequently, the number of effective antibiotic targets in bacteria is severely limited; every new active compound is warmly welcomed by the antibiotics researchers, especially if it highlights a new mode of action.

In the search for candidates which might be developed into such novel medicines the HZI enjoys a strong advantage: the institute has a unique collection of natural substances which has proved to be a highly effective source of drug candidates in the past. For example, the collection provided epothilone, which was approved as cancer medication last year. These substances are produced by myxobacteria, a group of microorganisms living in the soil.

The origin of the current success story is outlined by HZI biologist Dr. Herbert Irschik: "In our fundus we have three substances – myxopyronin, corallopyronin and ripostatin – which were isolated and characterised chemically and biologically. Already many years ago we recognized their unusual antibiotic effect. It was directed in an unknown manner against the bacterial RNA polymerase, i.e. the enzyme that reads the DNA of the pathogen.en/metas/glossary/entry/pathogen-1/ In eukaryontic cells, which human cells are also belonging to, the substances do not attack the RNA polymerase." However, before the initial evidence turned the substances into true antibiotic candidates, scientists had to reveal precisely how the growth of the bacteria was inhibited. "We began to develop a biotechnological processes which enabled us to produce and isolate the myxobacterial natural substances in large quantities," explains HZI chemist Dr. Rolf Jansen, who was also involved in the study.

Afterwards, the collaboration with the US research group at Rutgers University came off. The structural biologists studied the interaction of the HZI substances with the RNA polymerase. The results supported the indication that the natural substances block the bacterial RNA polymerase in a new manner: the natural substances append to another location within the RNA polymerase than the antibiotics previously investigated.

They attach to the enzyme – which looks like an open crab claw – directly at its joint position. Subsequently the enzyme is no longer able to open the claw. By this mechanism of action the active substances prevent the RNA polymerase from adhering to the DNA - reading of the genetic materials is suppressed completely. This new mechanism also operates in bacteria that are resistant to conventional antibiotics.

For Jansen and Irschik the results of the US researchers signalize that their substances now are facing a long process of development: " In their present form myxopyronin, corallopyronin and ripostatin are not yet applicable as antibiotics," explains Irschik. Further chemical development is now required, as Jansen adds: "Our natural agents are so-called chemical leads, which the chemists will modify in detail in order to increase their antibiotic action and minimize side-effects. This development will include extensive testing, which may take several years, before the new medicine will reach the hands of doctors finally."

Title of original publication:
The RNA Polymerase “Switch Region” Is a Target for Inhibitors. Jayanta Mukhopadhyay, Kalyan Das, Sajida Ismail, David Koppstein, Minyoung Jang, Brian Hudson, Stefan Sarafianos, Steven Tuske, Jay Patel, Rolf Jansen, Herbert Irschik, Eddy Arnold and Richard H. Ebright; Cell, 17 October 2008 135: 295-307. DOI 10.1016/j.cell.2008.09.033

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2009-01-09

When the hunters become the hunted

Braunschweig Helmholtz researchers show how bacteria drive immune cells to death

 Streptococcus pyogenesStreptococcus pyogenesThe immune system defends the body against pathogens. Macrophages are part of the first line of defence: they identify pathogens that have gained entry and destroy them. Bacteria that infiltrate the body are not powerless to resist the macrophages, however. Substances formed by the bacteria attack the macrophages, an attack that they sometimes fail to survive.

Eva Medina and her Infection Immunology research group at the Helmholtz Centre for

Infection research (HZI) in Braunschweig have discovered a new mechanism that leads to the destruction of macrophages. The results have been published in the current issue of the scientific journal Cellular Microbiology.

 

Macrophages identify bacteria, fungi and viruses that can make the body ill. They

absorb these germs in order to combat them. Inside the cell they destroy the intruders and use chemical messenger substances to draw further immune cells into the source of infection. If the macrophages are unable to defend themselves against the bacteria, then the bacteria gain the upper hand – the infection spreads.

 

Eva Medina and her research group at the HZI investigated the manner in which the bacteria

Streptococcus pyogenes attacks the macrophages. The findings came as a surprise to the researchers: the bacteria destroy the power plants of the macrophages, the mitochondria. As a result, energy supplies collapse and the cells die. In their experiments the researchers identified the previously unidentified mechanism that leads to the destruction of the mitochondria and subsequent cell death.

 

The process commences with substances produced by the bacteria that penetrate the cell walls of the macrophages. "Bacteria produce these so-called cytolysines continuously in order to prepare themselves for meeting our immune defence system," says Eva Medina. The researchers attempted to block the holes in the membrane of the macrophages and thereby save the cells. Although this proved successful, the cells died nevertheless. Medina's team identified the reason for this after some time: the bacteria had not only penetrated the cell wall, in the process they had also damaged the "cell power plants", the mitochondria. "Normally, the macrophages have learned to evade these cytolysines and neutralise them. However, the holes in the membrane trigger stress in the cells and also inhibit the mitochondria inside the cell. Finally, they give up and cease producing energy," says Medina.

 

That which results in death for the macrophages aids the bacteria in the infection. "The bacteria kill the macrophages insidiously from a distance. The body's first line of defence collapses. The cell death of the macrophages results in tissue damage and the bacteria are able to spread out more easily," says Medina. "By the time the immune system realises that something is wrong, it is too late."

 

Original article: Oliver Goldmann, Inka Sastalla, Melissa Wos-Oxley, Manfred Rohde and Eva Medina: Streptococcus pyogenes induces oncosis in macrophages through the activation of an inflammatory programmed cell death pathway, Cell Microbiol 2009, 11(1):138-155

 

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2009-02-16

When acute hepatitis develops into chronic hepatitis

Researchers at the Helmholtz Centre in Braunschweig demonstrate how the immune system reacts to a hepatitis B infection

Robert Geffers und Carlos A GuzmanHepatitis B is the most prevalent infectious disease in the world. It results in either an acute infection or, in rare cases, it can develop into a chronic disease. Researchers at the Helmholtz Centre for Infection Research (HZI) in Braunschweig have now examined the way in which the immune system reacts differently to both chronic and acute hepatitis B. To achieve this, Carlos A. Guzmán, Head of the “Vaccinology and Applied Microbiology” working group and Robert Geffers, Head of the “Gene Expression Analysis” platform, examined the incidence and species of special defence cells, T helper cells, along with their role in the development of the disease in conjunction with their Indian colleagues. With the aid of genetic analysis, they showed how the genes in these immune cells are regulated differently according to the development of the disease. These new results can help doctors to discover whether an infection is curable or whether by settling in the liver, it will develop into a chronic case. These results are now published in the scientific journal, “Hepatology”.

 

Approximately 300 to 420 million people (5 to 7% of the world’s population) have a chronic hepatitis B infection. India is one of the countries, in which hepatitis B is very common. A differentiation is made with the development of the disease between acute and chronic hepatitis B. The most common symptom of an acute infection is jaundice. In 5% of the infections, the disease becomes chronic, that is to say, the viruses remain in the liver. If left untreated, chronic hepatitis B can lead to a change in consciousness, cirrhosis and cancer of the liver. Until today scientists have not fully understood the role that the immune system plays in characterising an acute or chronic hepatitis B infection.

 

A decisive factor in achieving an appropriate immune reaction is the quick mobilisation of immune cells. These specifically attack the infected liver cells without destroying any unnecessary liver tissue in the process. Subspecies of the T helper cells play a decisive role in achieving this necessary balance between immunological defence and tolerance: effector T cells and regulatory T cells (Treg). Whilst the effector T cells fight a virus infection and kill off the infected host cells, the Treg cells shut down an immune reaction and cut off the effector T cells. They counteract any destruction of the tissue.

 

The international team of research scientists examined how these T helper cells influence the development of the hepatitis B disease. To this end, they took blood samples from Indian patients with hepatitis B and compared the extent to which the altered incidence of the T cell subsets in the blood influences the development of the illness and which genes are responsible for this.

 

Guzman’s and Geffers’s teams were able to show that, with acute hepatitis B, the effector T cells are extremely active and destroy infected host cells. Treg cells prevent effector T cells damaging healthy liver tissue during this stage of the infection. On the other hand, T effector cells are largely inactive with chronic hepatitis B infections: the Treg cells prevent an immune reaction and, in doing so, increase the number of hepatitis B viruses that are able to live in the organ. The immune system’s constant struggle against the virus leads to a slow destruction of the liver tissue. The researchers checked their observations with gene activity: They demonstrated that more that one hundred genes in effector T cells are regulated differently in an immune reaction to acute hepatitis B than to a chronic case.

 

“The molecular mechanisms and the specific gene activities of a hepatitis B infection were unknown up until now. We now have a much better understanding of how acute and chronic hepatitis B infections develop and which processes are involved”, says Carlos A. Guzmán. “With gene analysis we are able to further investigate the molecular links, which, in many ways, are a reason for the clinical observations”. The doctor thus has an opportunity to improve his diagnosis with so-called “marker genes” and to improve his treatment of the patients with targeted, immunotherapeutic measures”, says Robert Geffers, who conducted the gene analysis of the blood tests.  

 

Article: Nirupma TrehanPati, Robert Geffers, Sukriti, Syed Hissar, Peggy Riese, Tanja Toepfer, Jan Buer, Manoj Kumar, Carlos A. Guzman, Shiv Kumar Sarin. Gene expression signatures of peripheral CD4+ T cells clearly discriminate between patients with acute and chronic hepatitis B infection. Hepatology 2009. DOI 10.1002/hep.22696

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2009-03-02

Help for children with sick hearts

Scientists from the HZI discover the causes of rheumatic heart disease

 Kollagenbindung G52 und WildtypEach year, around 15 million children fall ill with rheumatic heart disease worldwide; half a million of them die as a consequence. At the beginning of the medical cases of these children stands a simple throat infection with streptococcus – spherical bacteria responsible for causing a range of different infections. However, it is only certain streptococcal strains that trigger a whole chain of reactions in the body that culminates in the life-threatening rheumatic heart disease. These bacteria carry a special protein sequence, the so-called PARF motif, on their surface. In the renowned journal PLoS ONE Singh Chhatwal and his colleague Patric Nitsche-Schmitz of the Helmholtz Centre for Infection Research (HZI) in Braunschweig illustrate the role played by PARF in the development of rheumatic heart disease. With this knowledge they are developing a test system that is able to recognise and prevent the disease at an early stage.


"PARF means 'peptide associated with rheumatic fever'," explains Nitsche-Schmitz. "It is a small section from a bacterial surface protein , which is used by the streptococcus to adhere to our cells and cause disease." Rheumatic fever develops from harmless sore throats amongst children in India, Australia and Africa in particular. The reason: inadequate medical treatment: if children with a streptococcus infection in the throat receive no or inadequate antibiotic treatment, then the surviving bacteria with the PARF sequence on their surface will adhere to their collagen. Collagen is present throughout the body – as a major component of bone and cartillage it determines shape and structure of our body  and it strengthens the connective tissue of the skin, the heart valves and blood vessels with its high resistance to tensile forces. Adhesion of PARF-bearing streptococci  to  collagenconfuses our immune system and our body's defence system not only targets the bacteria, but also healthy and vital collagen. The auto-immune disease rheumatic fever breaks out. If this in turn also fails to be treated correctly, the consequence is rheumatic heart disease: the heart valves, rich in collagen, become inflamed and cease to function.

Overall, only around five percent of all throat infections with streptococci result in an auto-immune disease. In order to filter out these five percent and treat them at an early stage, the Braunschweig infection researchers are developing a simple test strip that reacts to the PARF motif. "We hope that this will soon give us a test system that we can use for examination of children on a routine basis," says Singh Chhatwal: "This would save the lives of a lot of children."

Article: Dinkla K, Talay SR, Mörgelin M, Graham RMA, Rohde M, et al. 2009 Crucial Role of the CB3-Region of Collagen IV in PARF-Induced Acute Rheumatic Fever. PLoS ONE 4(3): e4666. doi:10.1371/journal.pone.0004666

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2009-03-02

When necessary, the lung slows down the immune system

HZI researchers explain the control of the T cell reaction in lung alveoli

 Labor_BruderThe lung’s mucous membrane comes into contact daily with thousands of molecules – many of them are harmless and many are threatening. In the latter case, defence mechanisms need be activated. If defence overshoots the mark, then it has to be restricted. Moreover, the cells in the pulmonary alveoli, the so-called lung air sacs, can co-decide how the immune system should react. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig have now discovered a communication channel between the pulmonary alveoli cells and the immune system’s defence cells, the T cells. The researches will publish their findings today in the “American Journal of Respiratory and Critical Care Medicine”, the leading journal in the field of lung diseases. “The regulatory effect of the lung cells on an immune reaction has been completely underestimated up until now”, states Dunja Bruder, Head of the “Immune Regulation” working group at the HZI. Now the researchers know how the epithelium cells in the lung reach the immune system.

 

“The cells in the lung’s mucous membrane are able to balance the immune reaction. They can work to aid or repress the inflammation, dependent on the messengers that they excrete”, says Marcus Gereke, a researcher in Dunja Bruder’s working group.  For example, if the cells secrete TGF-beta, a messenger that represses inflammation, they are in the position to calm the immune system. Then regulatory T cells, so-called Tregs (reg. T cells) are allowed to develop there. These Tregs (reg. T cells) have the ability to attenuate the inflammatory reactions. This way the lung can be protected from an aggressive immune reaction that would endanger the respiratory function.

 

The mucous membrane cells can also increase inflammations by giving the signal to the pathogen defence. To this end, the mucous membrane cells appear on the fragmented surface of a pathogen, which can be identified by T cells. The T cells then connect to specific defence, through which inflammations in the lung’s mucous membrane can be elicited.

 

“For this reason, the mucous membrane cells are surprisingly an important part of the immune defence in the lung”, says Bruder. “These findings are important basic principles for the development of new, tailor-made therapies in the field of chronic lung diseases such as asthma and COPD, chronic obstructive pulmonary diseases. In the future the researchers want to try and identify further messengers that repress inflammation and to engage in more specific cell communication, in particular, to stimulate regulatory T cells and, in doing so, alleviate inflammatory reactions.    

 

Title of the original publication:

Marcus Gereke, Steffen Jung, Jan Buer and Dunja Bruder: Alveolar Type II Epithelial Cells Present Antigen to CD4+ T Cells and Induce Foxp3+ Regulatory T Cells”; Am J Respir Crit Care Med Vol 179. pp 344–355, 2009

 

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2009-03-17

Brothers in Arms

Researchers from Helmholtz-Centre in Braunschweig and immunologists from Magdeburg investigate the connection of flu and pneumonia.

Influenza, or flu, is an unpleasant affair with fever, cough, as well as head and body ache. When this illness is further complicated by a bacterial pneumonia, a harmful superinfection develops. Until now, researchers thought that the flu facilitates an infection with pneumonia bacteria because it leads to a decrease of immune cells in the blood and thus impairs the body's defenses. A joint venture from researchers from the Helmholtz-Centre for Infection Research (HZI) in Braunschweig, the Otto-von-Guericke-University in Magdeburg, and the Karolinska institute in Sweden have taken an in-depth look at the connection between flu infection and pneumonia. Their results, recently released in the scientific journal “PLoS One”, have disproven a common theory about flu-like pneumonia.

 Influenza_Virus 

Some viral infections trigger a decrease of immune cells in the blood – a so-called "lymphopenia". The reasons behind it and whether this is the case with influenza are unknown. To investigate the latter, HZI researchers infected mice with flu viruses and measured the amount of immune cells in the animal's blood every day. Some days later, flu-infected mice received a dosage of pneumonia bacteria usually harmless for healthy mice. While the flu-infected mice did develop a superinfection & subsequently died, surprisingly, they were not suffering from lymphopenia. The healthy, non-flu-infected mice defeated the bacteria successfully and recovered. 

 

To discover whether a lack of immune cells encourages an infection with pneumonia bacteria in general, an artificial drug-induced lymphopenia was established in the mice. Without infecting these lymphopenic mice with flu viruses, they received pneumonia bacteria. Despite a severe lack of immune cells, the mice recovered completely.

 

With these results, the researchers could show that influenza facilitates and intensifies an infection from pneumonia bacteria, while disproving the common idea that this is caused by a lack of immune cells. "This result was an enormous surprise for us because it directly contradicts widespread assumptions", says Sabine Stegemann, researcher in the groups "Immune regulation" at the HZI and "Molecular Immunology" at the Otto-von-Guericke-University in Magdeburg.

 

"Now we want to understand the reasons for the increased susceptibility", says Matthias Gunzer, head of the group in Magdeburg. "It could be an interplay of weakened mucous membranes and scavenger cells that induce ideal conditions for pneumonia bacteria to create a deadly lung infection. Another reason may be a reaction of the host immune system: It disables hyperactive flu-fighting immune cells to inhibit destruction of healthy lung tissue. "The immune system keeps itself under control and that makes it easy for pneumonia bacteria to infect the lung", says Gunzer.



Article: Stegemann S, Dahlberg S, Kröger A, Gereke M, Bruder D, Henriques-Normark B, Gunzer M. Increased Susceptibility for Superinfection with Streptococcus pneumonia during Influenza Virus Infection Is Not Caused by TLR7-Mediated Lymphonia. 2009 PLoS ONE 4(3): e4840. doi:10.1371/journal.pone.0004840

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2009-03-18

When intestinal bacteria go surfing

HZI researchers identify molecular signal pathway in diarrhoea illnesses.

 EHECThe EHECs adhere to the surface of the mucosal cells and alter them internally: a part of the cellular supportive skeleton - the actin skeleton - is rearranged in such a manner that the cell surface beneath the bacteria forms plinth-like growths, so-called pedestals. The bacteria are securely anchored to this pedestal; the pedestals, in contrast, are mobile. This enables the bacteria, seated upon them, to surf over the cell surface and reproduce upon it, without being flushed from the intestine. But how do the bacteria bring the host cells to convert the actin skeleton? Researchers at the Helmholtz Centre for Infection Research (HZI) have now identified the signal pathway that leads to the formation of this pedestal.

"Prerequisite for this signal pathway is a special secretion system - a sort of molecular syringe, through which the bacteria insert entire proteins in the host cell," explains Theresia Stradal, head of the Signal Transduction and Motility research group at HZI. Two factors, Tir and EspFU, are brought into the host cell from the bacterium for pedestal formation. Following this, the host cell presents Tir on its surface; the bacterium recognises "its" molecule Tir and adheres to the host cell. EspFU then triggers the signal for local actin conversion.

"It has been unclear thus far how the two bacterial effectors Tir and EspFU enter into contact with one another in the host cell," says Theresia Stradal. Her research group has now found the missing link: "The molecule comes from the host cell, is called IRSp53 and gathers on the cell surface, directly beneath the bacteria sitting on it," explains cell biologist Markus Ladwein, who is also involved in the project. IRSp53, then, establishes the connection between Tir and EspFU. It ensures that actin conversion is concentrated locally. Together with the biochemist Dr. Stefanie Weiß, a former post-graduate student with the research group, Markus Ladwein also provided the counter evidence: "Cells in which IRSp53 is lacking are no longer able to form pedestals for the bacteria."

The signal pathway clarified by the Braunschweig researchers – published today in the journal Cell Host & Microbe – is a good example of how pathogenic bacteria develop progressively with their host. With the aid of bacterial factors, they therefore manage to simulate signals and set in motion complex processes in the host, which they then abuse for their own purposes.


Title of original publication:

IRSp53 Links the Enterohemorrhagic E. coli Effectors Tir and EspFU for Actin Pedestal Formation. Stefanie M. Weiss, Markus Ladwein, Dorothea Schmidt, Julia Ehinger, Silvia Lommel, Kai Städing, Ulrike Beutling, Andrea Disanza, Ronald Frank, Lothar Jänsch, Giorgio Scita, Florian Gunzer, Klemens Rottner, and Theresia E.B. Stradal. Cell Host Microbe. 2009 Mar 19;5(3):244-58.

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2009-03-26

The host makes all the difference

Braunschweig Helmholtz researchers demonstrate the role of the host in influenza illnesses.

 Schughart MausFor some people it is a certainty: as soon as the annual flu season gets underway, they are sure to go down with it. It is little comfort to know that there are other people who are apparently resistant to flu or who overcome the illness after just a couple of days. It is precisely this phenomenon that is now being investigated by researchers at the Helmholtz Centre for Infection Research (HZI), using various strains of mice. "Where there are many scientific works dealing solely with the flu virus, we have investigated how the host reacts to an infection," says Klaus Schughart, head of the Experimental Mouse Genetics research group. In infection experiments the researchers have now discovered that an excessive immune response is responsible for the fatal outcome of the disease in mice. This overreaction has genetic roots. The findings have now been published in the scientific magazine PLoS One.

For their investigations the researchers injected seven different inbred mouse strains with the same quantity of type Influenza A flu viruses. All of the animals within one mouse strain are genetically identical, like identical twins. However, one strain differs from another just like different individuals in the human population. To their surprise, the researchers were able to identify strong differences in the progression of the influenza between the seven strains. In five of the strains the illness was mild: the animals lost weight, recovering completely after seven to eight days. However, in two of the mouse strains the animals lost weight rapidly and died after just a few days.


The researchers looked for reasons for these differences: they investigated how the immune system of the animals responds to the virus. "The mice die from their own immune defences, which are actually supposed to protect them against the virus. The immune system produces too many messengers, which have a strong activating effect on the immune cells. These cells then kill tissue cells in the lungs that are infected with the virus," says Schughart. At the same time, these overactive cells also destroy healthy lung tissue. In mice that died the researchers also found one hundred times more viruses than in animals that survived. "It appears that the animals have specific receptors on their cells that make them more receptive to a severe viral infection." Flu infections in humans could take a similar course, here too, genetic factors could favour a severe progression of the illness. "It is only now that we are beginning to understand the role played by the genetic factors of the host and what increased receptiveness means in the case of influenza," says Schughart.


Every year between 10,000 and 30,000 people in Germany die from influenza, the majority via pathogens of the Influenza A type. There are various sub-types of the main type A, in which the composition of the virus envelope differs. H1N1 and H3N2 are the most widely-distributed flu strains amongst humans, H5N1 the familiar avian flu virus. The H stands for the protein haemagglutinin, with which the virus latches onto the cells of the airways, infecting them. In order for the newly-created flu viruses to leave the host cells, in turn, they require neuraminidase (N). To evade an immune response the virus changes the H and N characteristics constantly. Sometimes light, sometimes heavy: the result is a completely new virus type with a new number, with the consequences generally a severe global flu pandemic.

Article: Srivastava B, Błażejewska P, Heßmann M, Bruder D, Geffers R, et al. 2009 Host Genetic Background Strongly Influences the Response to Influenza A Virus Infections. PLoS ONE 4(3): e4857. doi:10.1371/journal.pone.0004857

 

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2009-04-27

Hepatitis B vaccine at low prices

Braunschweig-based Helmholtz researchers publish economical method for acquiring vaccines – help for poorer countries.

 FermenterInfection with the Hepatitis B virus (HBV) continues to represent a significant problem worldwide: over two billion people are infected and 350 million suffer from chronic Hepatitis B. One of the countries in which Hepatitis B frequently occurs is India. In a German-Indian collaboration researchers from the Braunschweig Helmholtz Centre for Infection Research (HZI) have now developed a new method that enables large quantities of Hepatitis B vaccine to be generated at particularly low cost. The findings have been published in the free online scientific journal Microbial Cell Factories. The information is accessible to all and is not subject to patent. "We have published this information in an open access journal and waived patents, thus making it freely accessible to all," says Ursula Rinas of HZI, who heads the German team involved in the project.

 

Until the beginning of the 1980s researchers isolated empty, uninfected viral envelopes from the blood of patients suffering from Hepatitis B, with these subsequently processed to form a vaccine. It soon became apparent that the provision of one component of the viral envelope was sufficient for a successful vaccination. Following this, the component was produced artificially in laboratories using the familiar baking yeast Saccharomyces cerevisiae, where it was then isolated on a large scale. The Hepatitis B vaccine was consequently the world's first recombinantly-produced vaccine.

 

For many people in poorer countries medicines are too expensive. The use of the recombinant Hepatitis B vaccine is not possible in these countries due to the costs involved. A further problem is patents that prevent medicines from being copied and marketed cheaply for decades. It is only when these patents lapse that these so-called generic medicines can be manufactured cheaply.

 

The German-Indian collaboration aimed to develop a new Hepatitis B vaccine that could also be accessible to people in poorer countries. The researchers attempted to raise the yield of virus particles with the aid of another producer and subsequently reduce the costs. They turned to the yeast fungus Pichia pastoris, modifying the fungus in such a way that, growing on a specific medium, it produces the component of the viral envelope. The result was a pleasing one for the researchers: "With one litre of yeast culture we can produce around 300,000 vaccination doses for children. This is the highest-known yield for this vaccine to date and around seven times as much as was previously known," says Rinas.

In future the researchers aim to use the same system to produce a vaccine for Dengue fever.

 

Original article: Simple high-cell density fed-batch technique for high-level recombinant protein production with Pichia pastoris: Application to intracellular production of Hepatitis B surface antigen. Chandrasekhar Gurramkonda, Ahmad Adnan, Thomas Gabel, Heinrich Lunsdorf, Anton Ross, Satish Kumar Nemani, Sathyamangalam Swaminathan, Navin Khanna and Ursula Rinas. Microbial Cell Factories 2009, 8:13 (10 Feb 2009)

 

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2009-05-11

EU awards three million Euro for pneumonia research

HZI coordinates international consortium of scientists for development of new drugs and vaccines against pneumococcal diseases.

 PneumokokkenPneumonia infections are not only a problem of developing countries. In Germany more than 60.000 people die annually due to this disease, which is mostly caused by the bacterial species "Streptococcus pneumoniae". Combating pneumococcal infections is getting more and more difficult and current vaccines mediate only partial protection. 13 international research institutions representing 10 countries in Asia, Europe and South America have joined forces with the aim to develop new antibiotics and vaccines to fight pneumococcal infection. The department of Microbial Pathogenicity of the Helmholtz Centre for Infection Research (HZI) in Braunschweig is coordinator of the project named "CAREPNEUMO", which is running for three years and funded with 3 Million Euro by EU.

 

Antibiotic resistant bacterial pathogens are a serious problem: many drugs which successfully eliminated an infection in the past have become ineffective. The emergence of multiresistant bacteria is a severe problem and a variety of antibiotics are now ineffective. Singh Chhatwal, head of the department "Microbial Pathogenicity" at the HZI: "In France and Spain, about half of the pneumococcal isolates are resistant against at least one antibiotic”.

 

The two currently available pneumococcal vaccines have the disadvantage that not all of the more than 90 pneumococcal subspecies, named serotypes, are covered. Prof. Singh Chhatwal said "while vaccination reduces spreading of these seven serotypes it has unfortunately led to appearance of uncommon pneumococcal serotypes. In addition, in Germany and United States for example, the prevalent serotypes are different to those serotypes commonly found in India, which complicates worldwide treatment and prevention strategies. "Therefore, we have to find alternatives for treatment and prevention of pneumococcal infections", says Singh Chhatwal. For this reason, he has initiated the research consortium CAREPNEUMO.

 

The objectives of the consortium is divided into three research projects: At first, scientists want to identify and characterize pneumococcal serotypes, which are of main importance worldwide. Afterwards, pneumococcal escape of human immune system and induction of pneumonia will be investigated. Then, based on the acquired knowledge, new therapies, antibiotics and vaccines will be developed.

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2009-05-11

Thus the bile does not overflow

HZI-Scientists have elucidated which bacteria block artificial bile ducts

 Streptococcus anginosusStreptococcus anginosusA consequence of the different cancers of the hepatobiliary system is blocked bile ducts. However, artificial catheters known as ‘stents’ can remediate this problem. Stents are medical implants which reopen narrowed bile ducts to allow the outflow of bile. However, bacteria colonize these catheters forming dense communities, so-called biofilms. Inside these biofilms, bacteria are not only protected from the immune response initiated by the host but also from antibiotics. Since the bacterial community is unable to be controlled via antibiotics, the catheters become blocked by the biofilms, which then have to be exchanged on a regular basis, an invasive process.

 

Scientists of the Helmholtz-Centre for Infection Research (HZI) in Braunschweig have analyzed biliary stents from patients being treated at the medical clinics in Salzgitter and Braunschweig. They would like to know which bacteria inhabit these stents so that such knowledge can facilitate the development of medications tailored to combat against development of these biofilms. The HZI-Scientists identified specific bacterial species as main colonizers of these stents. In addition they statistically evaluated the composition of the bacterial communities of the catheters. Their results have now been published by the scientific journal “International Society for Microbial Ecology”.

 

The Scientists of the HZI Department “Microbial Pathogenesis” used material from biliary stents of patients where old catheters had been replaced by new ones. For this reason, they collaborated with the Surgery Clinic of the Braunschweig General Hospital and the Department of Internal Medicine of the Klinikum Salzgitter. The Klinikum Salzgitter is the most specialized and experienced clinic for biliary stent replacement in the region, where each week patients receive new biliary stents. “This had the advantage that we could compare a huge set of samples” Dietmar Pieper, Group leader in the Department of Microbial Pathogenesis said. “This huge set of samples could only be analyzed as we did not try to culture the bacteria on plates, but used sophisticated culture-independent methods” Pieper said. The main goals of the scientists were to determine the composition of the bacterial communities in different biliary stents, their interactions with each other and which bacteria most often occur.

 

“Certainly, there are significant differences between the patients and consequently between the communities” Pieper said. In general, however, the Scientists could identify recurrent dominant colonizers, such as the bacterium Streptococcus anginosus. Interactions and dependencies among the bacteria were gathered by statistical means. “We could show that the colonization of the stents followed principles ressembling those known for biofilm development of dental plaques” Pieper said. 

 

In the future, the scientists will analyze the influence of different environmental factors such as a healthy lifestyle on the composition of such communities. “With these results an important cornerstone was laid towards the development of new methods and medications”, Pieper said.

Originalartikel: Characterization of the complex bacterial communities colonizing biliary stents reveals a host-dependent diversity. Britta K Scheithauer, Melissa L Wos-Oxley, Björn Ferslev, Helmut Jablonowski and Dietmar H Pieper. ISME J advance online publication, April 9, 2009; doi:10.1038/ismej.2009.36

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2009-06-02

The whole world of infection research

Helmholtz internet portal for researchers and journalists

FahnenFahnenThe web site www.infection-research.de is being relaunched with a new look: it is the first internet portal worldwide on the subject of infection research. The Braunschweig Helmholtz Centre for Infection Research (HZI) operates the web site which, in addition to an extensive job market for infection researchers, also offers eight further information areas. "The portal aims to offer scientists and journalists extensive information and evolve into the leading internet meeting point for the infection research scene," says Rudi Balling, Scientific Director at HZI and initiator of the portal. There are currently around 6,000 scientists and science journalists worldwide using the site, developed in 2007, on a regular basis. To date the texts have been exclusively in English, for the first time now selected German translations are also to be offered.

Service for scientists and journalists

Following the relaunch the web site not only offers a new layout, but also significantly more service:

- A job database, containing nearly all worldwide vacancies in the field of infection research. This may be accessed free of charge.

- A comment function enables scientists and journalists to discuss current themes online.

- Concise information and extensive links offer journalists in particular a precise overview of the most globally significant infectious diseases and the current status of research. The newly-established bilingual aspect should be a further aid in this.

- The range of graphics created specifically for PowerPoint use should aid scientists in the graphic layout of their presentations and papers – professionally created illustrations of cells or receptors are available for free downloading. This will enable the scientists to save time, as well as considerably increasing the aesthetic quality of their own slides.

Independent information

Scientific independence and an international approach are paramount at infection-research.de. "The content of the site is compiled by an international editorial team consisting of biologists, medical practitioners and freelance science journalists. The focus is neither upon national themes nor Helmholtz subjects. If a theme is good and significant, then it will appear on infection-research.de," explains Hannes Schlender, Head of Press and PR at HZI. "With this initiative we aim to reinforce the exchange of thoughts and ideas between the scientists, whilst at the same time making a difficult subject accessible to interested journalists," says Schlender.

Further areas are to be established in the coming months. In future there will also be animations of significant infection biology processes, which will be available for download. In addition, an international editorial board is currently being established, the purpose of which will be to guarantee the independence of the content and monitor the quality of editorial work.

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2009-06-09

GARP makes the difference

Researchers develop key brake for immune cells in petri dish – hope for easier organ transplantation?

 Crosstalk Scientists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany and the Medical School Hannover, Germany (MHH) have succeeded in treating immune cells in a way that enables them to inhibit unwanted immune reactions such as organ rejection. Their results have now been published in the current issue of the scientific journal “Journal of Cellular and Molecular Medicine”.

The immune system keeps us healthy: day and night it protects us against invading and harmful pathogens. But this fulltime surveillance can also turn into a problem, for example after an organ transplant. The immune system recognizes the new organ as “foreign” and starts fighting it. In the end, the life-saving transplant will be rejected. Until now, only special drugs have managed to keep the immune system silent and thus inhibit organ rejection.

Theoretically, these drugs are not necessary because the immune system has its own unique “peace makers”: regulatory T cells (Tregs), a special group of helper T cells, an important cell type of the immune system. Tregs inhibit immune reactions and are thus of special medical interest. Until now, distinguishing between Tregs and helper T cells has represented a problem for scientists. Now, in co-operation with the Medical School Hannover, researchers from the Helmholtz Centre for Infection Research in Braunschweig have identified a molecular factor that plays an essential role in Treg function. This protein constitutes the key difference between Tregs and helper T cells. Furthermore, the scientists have also generated Tregs from helper T cells that permanently maintained their characteristics.

The key to Tregs is called “GARP”. Michael Probst-Kepper is a researcher in a junior research group that is financed by the German Volkswagen foundation, he works at both HZI and MHH. He has now deciphered the special role of the GARP protein. Until now, scientists had only little distinguishing features to aid them in separating T cells that trigger a transplant rejection from those that inhibit such a reaction: they mainly looked at molecular features that both cell types have – the one more, the other less. “It’s like looking at two cars that appear to be the same. Except that one is capable of driving while the other doesn’t drive anymore. But you cannot see that from the outside,” says Michael Probst-Kepper. He deciphered the role of GARP: this new-found factor only exists in Tregs and initiates a complex network of various molecules. “If you don’t want a car to drive anymore, you pull the key out and cut the petrol pipe. GARP does the same: it prevents Tregs from stepping on the gas.”

The scientist artificially inserted GARP into those T cells that start an immune reaction against transplants. The result was a substantial advance for medicine: the transplant-rejecting T cells developed permanently into Tregs – those cells that inhibit the activation of aggressive T cells and thus prevent organ rejection. Furthermore, the researchers also furnished the counter evidence: Michael Probst-Kepper muted the GARP gene in Tregs. As a result, the Tregs lost their “peace making” characteristics. “The cells could start driving again,” he says. “With this study we were able to show the complexity of the Treg system for the first time, developing a powerful tool for medicine to develop new therapies and drugs.”

 

Article: GARP: a key receptor controlling FOXP3 in human regulatory T cells. Probst-Kepper M, Geffers R, Kröger A, Viegas N, Erck C, Hecht HJ, Lünsdorf H, Roubin R, Moharregh-Khiabani D, Wagner K, Ocklenburg F, Jeron A, Garritsen H, Arstila TP, Kekäläinen E, Balling R, Hauser H, Buer J, Weiss S. J Cell Mol Med. 2009 May 13. [Epub ahead of print]

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2009-06-30

The tiny difference in the genes of bacteria

Researchers from Helmholtz Centre for Infection Research, Germany, develop new method for better diagnostic of diarrhea causing bacteria.

Hoefle VibrioEvery year, diarrhea causes around five million fatalities worldwide. Most people die due to pathogenic microorganisms, such as bacteria or viruses, which were ingested into the gastro-intestinal tract through contaminated drinking water or food. Determining which bacterium is causing the illness in those cases is sometimes very complex. In cooperation with Chilean researchers, scientists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, have now developed a fine-tuned diagnostic method. It is based on detecting short, repetitive DNA segments in the genome of bacteria. Every single bacterial strain has such characteristic repeats. “With this method we are able to identify bacterial strains as well as clarify their genetic relationships. Furthermore, we can show how new pathogenic variants develop,” says Manfred Höfle, researcher at the HZI. The results have now been published in the current issue of the scientific journal “Applied and Environmental Microbiology”. The work is part of the two European Union funded projects “Healthy Water” and “AQUA-chip”. Manfred Höfle is coordinator of both projects that deal with various aspects of the microbiological safety of both, drinking water and sea water.

 

Various bacteria that live in drinking water or sea water can cause severe human diseases. One of them are vibrios: its species Vibrio cholerae is more commonly known as the causative agent of Cholera that spread in Europe until the 20th century. Interestingly, not all Vibrio cholerae strains are pathogenic to humans. Only those strains cause severe diarrhoea known as Cholera that produce a certain bacterial toxin which attacks the intestinal wall. A less known, though also dangerous member of the genus Vibrio, is Vibrio parahaemolyticus. It is a highly contagious pathogenic germ with only a dozen ingested bacteria causing severe diarrhoea. This strain is a threat for the pacific region and reached the east coast of the United States in the 21st century. Since the end of the 1990s, Vibrio parahaemolyticus epidemics have led to thousands of cases of illness in Chile. In the future, due to ballast water or climate change, the species may also gain importance in Europe. As in the Cholera bacterium, various Vibrio parahaemolyticus strains exist with varying infectivity. Distinguishing those strains has been a challenge until now.

 

The newly developed method makes it now possible to characterize and distinguish hundreds of bacteria strains in a short time. The method is based on the existence of short, repetitive DNA segments in the genome of all living species. As in a tandem bike, those segments are lined up on the DNA strand, called “tandem repeats”. They are characteristic for every bacterial strain. To identify a certain strain, the HZI researchers use short DNA fragments, marked with certain dyes. Each dyed DNA fragment recognizes a single tandem repeat, binding at it. As a result, the researchers receive, for example, six red fragments binding a tandem of six repetitions. Then, the researchers analyzed the tandem repeats marked with dyed fragments: Every bacteria strain differs in pattern and size of the measured tandem repeats.

 

“With this method, we are able to differentiate more then 120 Vibrio parahaemolyticus strains,” says Manfred Höfle. This is important for infectious diseases in which it is necessary to know which strain is the causative agent. Further information are whether it is just one or more strains and where they derive from. The latter can help to prevent spreading of the disease with corresponding sanctions. “The intake of Vibrio parahaemolytics often occurs through raw clams that have filtered contaminated sea water. With this method, we are able to say from which clam species the germ originates.” The new technique can also be used to characterize other bacterial pathogens and to investigate how pathogenic bacteria evolve in the environment. “Hereby, this high resolution method makes an important contribution towards a fast and precise recognition of microbial pathogens with pandemic potential.”

 

Article: Multiple-Locus Variable-Number Tandem-Repeat Analysis for Clonal Identification of Vibrio parahaemolyticus Isolates by Using Capillary Electrophoresis. Erika Harth-Chu, Romilio T. Espejo, Richard Christen, Carlos A. Guzmán, and Manfred G. Höfle. Appl. Environ. Microbiol. 2009; 75: 4079-4088

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2009-07-20

The right messenger for a healthy immune response

Researchers from Helmholtz Centre for Infection Research, Germany, decipher special role of the messenger Beta-Interferon for immune responses.

 CrosstalkCells of the immune system communicate using molecular messengers. One group of these substances are interferons. During a virus infection, the immune system increases the production of interferons such as Beta-Interferon, thus alerting immune cells to combat the infection. Furthermore, Beta-interferon also has tumour fighting qualities and – used as a therapeutic against multiple sclerosis – is of major importance for medicine. Researchers from the Molecular Immunology group at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany have now shown that Beta-Interferon also plays a crucial role during an immune response: without Beta-Interferon immune cells are unable to show “wanted posters” of pathogens to other cells. As a consequence, these cells will not recognize the pathogen and the immune response does not start properly. The group’s results have now been published in the current issue of the scientific magazine “Journal of Immunology”.

 

During an infection, immune cells produce Beta-Inferferon. Interestingly, an immune response is even stronger when a low amount of Beta-Interferon has already been present before the infection occurs. Scientists call this behaviour “priming”. A healthy basal level of Beta-Interferon facilitates a faster immune reaction against microbial and viral threads. Researchers from the HZI have now managed to show why this is the case: Beta-Interferon is a key regulator and of vital importance in enabling the immune system to display fragments of pathogens, so-called antigens. Immune cells present these antigens on their surface and in this way communicate with one another: antigens are the “wanted posters” of the virus or the bacterium which has to be destroyed.

 

The researchers discovered the important role of Beta-Interferon in mice lacking the gene for Beta-Interferon. These mice displayed poor immune responses. “Without those knock-out mice we would not have been able to identify the impact of Beta-Interferon on the immune system,” says Siegfried Weiß, leader of the Molecular Immunology group at the HZI. His research assistant, the scientist Natalia Zietara, investigated what Beta-Interferon is doing in immune cells. She found a molecular factor that is pivotal in producing the pathogen’s profile and which is regulated by Beta-Interferon. The factor belongs to a group of proteins that is usually produced in conditions of stress. Without Beta-Interferon, no active stress protein – without stress protein, no wanted poster – without wanted poster, no immune response.

 

“We now have a far better understanding of how immune responses start, but also how diseases like autoimmune diseases may develop,” says Weiß: without Beta-Interferon, the immune system may not be able to learn how to tolerate itself during the embryonic phase and that it should not fight against self-structures. “Our findings can help to develop or improve new therapeutics to combat autoimmune diseases such as multiple sclerosis or cancer.”

 

Originalartikel: Zietara N, Lyszkiewicz M, Gekara N, Puchalka J, Dos Santos VA, Hunt CR, Pandita TK, Lienenklaus S, Weiss S. Absence of IFN-beta impairs antigen presentation capacity of splenic dendritic cells via down-regulation of heat shock protein 70. J Immunol. 2009 Jul 15;183(2):1099-109.

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2009-08-25

Casting out devils

Scientists from Helmholtz Centre for Infection Research are researching how salmonella kill tumours.

 Salmonellen-infizierter TumorSalmonella are regarded as bad guys. Hardly a summer passes without severe salmonella infections via raw egg dishes or chicken that find their way into the media. But salmonella not only harm us – in future they may even help to defend us against cancer. The bacteria migrate into solid tumours and make it easier to destroy them. Furthermore, in laboratory mice they independently find their way into metastases, where they can also aid clearance. In the scientific journal PLoS ONE, Sara Bartels and Siegfried Weiss of the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany now show how the bacteria migrate into tumours.

A messenger substance from the immune system is the door opener: It makes blood vessels in the cancerous tissue permeable; enabling the bacteria to conquer and destroy the tumour. Simultaneously, blood streams from the vessels into the cancerous tissue, a so-called necrosis develops – and the tumour dies. “This influx of blood was the starting point for our investigations,” says Siegfried Weiss, Head of the Molecular Immunology group at the HZI. “There is an immunological messenger present during bacterial elicited inflammation that causes this kind of reaction. We searched for it – and found it.”

This messenger is named after its role in the immune system: tumour necrosis factor, TNF-alpha for short. Immune cells produce TNF-alpha when recognising salmonella, thus alarming other immune cells. This inflammatory reaction leads to an increased blood vessels permeability an action that also occurs in a tumour: TNF-alpha has an easy task here because the blood vessels in cancer differ fundamentally from healthy arteries or veins. They are irregularly built, porous, partially with dead ends. A small amount of TNF-alpha is subsequently enough to dissolve the walls of the blood vessels in the tumour and allow the blood to stream into the cancerous tissue.The scientists hope to be able to modify salmonella so they can be used in tumour therapy. The aim is for the bacteria to migrate specifically into tumours and cause them to die.

The attractiveness of this way of destroying tumours is the lifestyle of salmonella. They can live almost everywhere, including tissues, which are badly supplied with blood and thus have hardly any oxygen supply. And it is precisely these areas that are scarcely reachable in a cancerous ulcer using common cancer therapies: chemotherapeutics cannot be transported to an area where there is no blood flow. And even radiation therapy requires oxygen for its reactions in the tissue.The phenomenon of bacteria attacking tumours has been known to scientists for a long time. However, a cancer therapy with potential pathogens has been unthinkable before now. The risk of the patient dying due to an infection was too high. “We have obtained an important indication of how bacteria migrate into tumours. We can now try to manipulate these bacteria to use them in cancer therapy without causing deadly infections,” says Sara Bartels.The results of her study will be particularly helpful in this: she was able to show that the release of TNF-alpha plays a part in enabling salmonella to colonise the tumour efficiently.

Subsequently, salmonella that is attenuated too strongly may no longer be able to migrate into the tumour because the immune system does not react properly and produces too little of the necrosis factor. “We need to find the right amount of bacteria aggressiveness, allowing the tumour to be colonised and destroyed without harming the patient,” she says. If the scientists succeed in accomplishing this feat, they may be able to take the next step forward: using salmonella to release therapeutic substances within the tumour and thus participate in its destruction. They could then penetrate deep within the tumour with the salmonella, reaching the very last cancer cells – a revolution in tumour therapy. “Our experiments are currently limited to absolutely basic research and experiments with laboratory mice,” says Siegfried Weiss, “it may take years before this method is usable for human patients.”

 

Original article: Leschner S, Westphal K, Dietrich N, Viegas N, Jablonska J, et al. 2009 Tumor Invasion of Salmonellen enterica Serovar Typhimurium Is Accompanied by Strong Hemorrhage Promoted by TNF-?. PLoS ONE 4(8): e6692. doi:10.1371/journal.pone.0006692

 

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2009-11-30

It takes two to infect

Structural biologists shed light on mechanism of invasion protein.

Bacteria are quite creative when infecting the human organism. They invade cells, migrate through the body, avoid an immune response and misuse processes of the host cell for their own purposes. To this end every bacterium employs its own strategy. In collaboration with a British research group, structural biologists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany and the University of Bielefeld, Germany have now elucidated one mechanism of Listeria bacteria. Two so-called invasion proteins are crucial for infection. Each binds a specific receptor on the surface of human cells, which stimulates the host cell to take up the pathogen. Normally, these receptor molecules exert a different function, for example the regulation of cell growth and wound healing. The group’s results have now been published in the current issue of the “Journal of Molecular Biology”.

 HZI 1010 gf sg 041

Spoiled meat is one of the sources for Listeria infections leading to listeriosis. Pregnant women, newborns and immune compromised people are susceptible for a severe progression of this disease. Firstly, the pathogen breaches the intestinal barrier and thus enters the body. The key for further spreading is the invasion protein internalin B that is located on the bacterial surface. On human cells, internalin B activates a receptor molecule called “Met”, thereby signaling the host cell to take up the pathogen. Inside the cell, Listeria uses the host cell’s nutrients and is somehow sheltered from an immune response.

 

Until now, the researchers did not know how the bacterial invasion protein activates the human receptor. To solve this question, the structural biologists from the HZI first analysed the crystal structures of the single internalin B molecule and of its complex bound to human Met. “In X-Ray structural analysis we noticed that in protein crystals two internalin B molecules align characteristically,” says Hartmut Niemann, assistant professor at the University of Bielefeld. Professor Dirk Heinz, head of the structural biologists at the HZI, explains: “This gave rise to the idea of a dimer – two congregated internalin B molecules – playing a pivotal role in the activation of the Met receptor.”

 

Minor changes in the internalin B molecule confirmed their hypothesis: inhibiting the congregation of two internalin B molecules prevented the activation of Met. On the other hand, strengthening the interaction resulted in particularly strong receptor activation.

 

These results may lead to the development of new protein drugs in the future. “Met plays a major role in the body, for example during wound healing,” says Heinz. “Thanks to the extraordinary ability of the internalin B dimer to strongly activate Met, therapeutics for improved wound healing may result someday.”

Originalartikel: Ligand-Mediated Dimerization of the Met Receptor Tyrosine Kinase by the Bacterial Invasion Protein InlB. Davide M. Ferraris, Ermanno Gherardi, Ying Di, Dirk W. Heinz and Hartmut H. Niemann. J Mol Biol. 2009 Nov 6. [Epub ahead of print]. doi:10.1016/j.jmb.2009.10.074

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2009-12-17

Invasion without a stir

HZI researchers redefine the invasion mechanism of Salmonella.

SalmonellenSalmonellenBacteria of the genus Salmonella cause most food-borne illnesses. The bacteria attach to cells of the intestinal wall and induce their own ingestion by cells of the intestinal epithelium. Up till now, researchers assumed that Salmonella have to induce the formation of distinctive membrane waves in order to invade these gut cells. Researchers from the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, now refuted this common doctrine. “Based on our data, the molecular mechanism of infection employed by Salmonella has to be revised,” says Klemens Rottner, head of the HZI research group “Cytoskeleton Dynamics”. The group’s results have now been published in the current issue of the scientific journal “Cellular Microbiology”.

 

Salmonella are highly adaptive bacteria. They can live in the presence and absence of oxygen and thus propagate in the gut. The ingestion by humans occurs mainly via contaminated egg dishes such as mayonnaise or raw milk products as well as meat or sausages. Infections with Salmonella lead to severe diarrhea and fever, particularly in patients harbouring a compromised immune system.

 

Although Salmonella are long-known pathogens, the precise mechanisms of infection are incompletely understood. The bacteria inject a protein cocktail using a “molecular syringe” into host cells, leading to dramatic rearrangements of cytoskeletal filaments below the cell membrane. As a result, membrane waves are formed, which enclose the bacteria, and apparently facilitate their invasion. Those characteristic membrane waves are called “ruffles”, the process is known as “ruffling”. Until now, researchers regarded the formation of these ruffles as absolutely essential for bacterial entry.

 

Salmonella invasion smallIn a collaborative effort, HZI research groups “Cytoskeleton dynamics” and “Signalling and Motility” now succeeded in shedding new light on the infection strategy of Salmonella. “We wanted to improve our mechanistic understanding of how Salmonella invade their host cells,” says Jan Hänisch, who performed most experiments in the course of his PhD-thesis. Cells that were engineered to lack those membrane ruffles normally induced during Salmonella infection still engulfed the bacteria. “We showed for the first time that membrane ruffles are not essential for the bacteria to penetrate the host cell membrane.“ Since ruffling was used so far as signature of successful host cell invasion by this pathogen, the usefulness of such methods has to be reconsidered.

 

Finally, the researchers discovered a new piece in the puzzle of Salmonella entry, called WASH. This novel factor promotes bacterial invasion by contributing to the formation of host cell cytoskeletal filaments important for entry. “Our results have significant impact on the molecular and mechanistic understanding of the infection strategy used by this pathogen,” says Rottner, “and on the development of novel strategies to screen for potential inhibitors of the entry process in the future.”

 

Original article: Molecular dissection of Salmonella-induced membrane ruffling versus invasion. Hänisch J, Ehinger J, Ladwein M, Rohde M, Derivery E, Bosse T, Steffen A, Bumann D, Misselwitz B, Hardt WD, Gautreau A, Stradal TE, Rottner K. Cell Microbiol. (2010) 12(1), 84–98. doi:10.1111/j.1462-5822.2009.01380.x

 

Download: The invasion of Salmonella (red) can occur with ruffles (arrows, upper picture) as well as without ruffles (lower picture). Scanning electrone microscope picture: Manfred Rohde (HZI).

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2010-01-26

Rejuvenating the old immune system

Researchers from HZI are investigating the development of novel therapies to make the old immune system young again.

Streptococcus pyogenesThanks to the progress in health care and improved living conditions, we live longer. The price we pay: Our immune system loses functionality with advance age and the susceptibility to infections increases. The members of the research group "Infection immunology" at the Helmholtz Center for Infection Research (HZI) in Braunschweig, Germany are investigating this aspect of aging using a mouse model that mimics the susceptibility to infection observed in elderly humans. By comparing the immune responses of both, young and old mice, to bacterial infection they found that the number of macrophages, one of the major cell populations involved in the elimination of infecting bacteria, decreases rapidly in aged mice. This decline in the number of fighters and the associated weakness of the immune defense may be responsible for the age-associated increase in susceptibility to infections. The HZI researchers have succeeded to enhance the resistance to an infection in aged mice by treating them with a macrophage-specific growth factor. This treatment increases the amount of macrophages in aged mice and improves their capacity to fight the infection. This study has been published in the current issue of the scientific magazine "Journal of Pathology".

 

The main task of the immune system is to protect the body against invading pathogens. For this purpose, a variety of different cell types and molecular factors work together in a complex network. Together, they compose a highly effective defense front line. As we are getting older, our immune system changes: infections are more frequent and more severe, some immune cell types lose certain properties and their functionality declines – in short: the immune system grows old. "Since the immune system protects our body against infections, to keep the immune system young and functional is a crucial factor for a healthy aging," says Eva Medina, head of the HZI research group "Infection Immunology".

 

Much research effort is now focused on identifying age-related changes in the immune function in the hope of developing intervention strategies. "These therapies aim to strength the resistance of the elderly against infectious pathogens," says Eva Medina. The researchers from the HZI have used young mice, age two to three months, and aged animals, older than 20 months (this is the equivalent of 70 to 80 human years) to investigate specific deficiencies in the immune function that lead to the age-related increased in susceptibility to infection with the bacterium Streptococcus pyogenes. This pathogen is an important cause of severe, life-threatening infections among the elderly population. While the young animals were able to combat the infection successfully, the old mice died even if they were infected with fewer bacteria.

 

Afterwards, the researchers investigated the immune mechanisms involved in the control of the infection that are functional in young mice but impaired in the aged animals. They focused their studies on macrophages because these cells are the first line of defense for combating  bacterial infections.  The scientists found that the amount of this cell type is highly reduced in the tissue of aged mice compared to young animals. As the amount of macrophages in the organs depends on the production of a specific growth factor, the researchers evaluated if treatment with this growth factor could induce repopulation of resident tissue macrophages in aged mice and increase their resistance during infection.

 

"The treatment made aged mice much more resistant and they could fight much better the infection. The results of our study indicate that repeated prophylactic administration of this growth factor can help to maintain the macrophage compartment in the elderly and the fitness of the immune system," says Oliver Goldmann, scientist in the HZI research group. "Understanding the changes occurring within an ageing immunes system that increase the susceptibility to infection is essential for developing  new strategies to to improve the capacity of the elderly immune system to fight and defeat pathogens."

 

Original article: Age-Related Susceptibility to Streptococcus pyogenes Infection in Mice: Underlying Immune Dysfunction and Strategy to Enhance Immunity. Goldmann O, Lehne S, Medina E. J Pathol (2009 Nov 17). DOI: 10.1002/path.2664

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2010-03-02

Small molecule with high impact

Researchers from HZI vaccine department examine new adjuvant to improve vaccinations.

 

ELI_SpotThe adjuvants present in vaccines have a bad reputation. For most people, they are only unnecessary compounds within a medicinal product. This is a misunderstanding since adjuvants have a critical impact on the success of a vaccination. In the best case scenario, one single vaccination shot would be now sufficient for conferring life-long protection. Researchers from the "Vaccinology and Applied Microbiology" Department at the Helmholtz Center for Infection Research (HZI) in Braunschweig, Germany have now found a new molecule with the capacity of improving responses to vaccines. The synthetic compound, the so-called c-di-IMP, might be more than just a potent vaccine enhancer. The scientists expect to create new vaccination strategies based on c-di-IMP. The group's results have now been published in the current issue of the scientific journal "Vaccine".

 

Vaccines are one of the most powerful tools against infectious diseases. They protect against an infection by preventing the infection to arise. In a typical vaccine, attenuated or killed pathogens or just some of their sub-cellular components are injected into the body. The immune system responds to those foreign components, producing antibodies and/or killer cells, which are able to fight the pathogen, as well as memory cells. The latter recognize the true pathogen after host infection, thereby promoting a specific and rapid response able to prevent the establishment of a disease.

 

However, the immune system often reacts only weakly to the attenuated pathogens or their fragments present in a vaccine. Thus, partial or short-life protection is usually stimulated. The adjuvants by themselves do not trigger an immune reaction, but given as components of a vaccine, they modulate and enhance the immune responses elicited, thereby providing a stronger, early and long-lasting protection. While searching for new adjuvants, the vaccine researchers at the HZI have now found the molecule "c-di-IMP".

 

"This molecule leads to a strong immune response and it is significantly more effective than known adjuvants," says Rimma Libanova, who is examining the molecule in her PhD thesis. To investigate how it works, she vaccinated mice with a harmless protein, which acts as a foreign structure for the immune system of a mouse. Like during a vaccination against a virus or bacterium, an immune response starts against the protein – without the danger of a real infection. One group of mice received the vaccine with the enhancer molecule, the other without the additive. After 42 days, she analyzed the immune reaction of the mice to the foreign protein. "We found a strong immune reaction in mice that received the optimized vaccine. Furthermore, we measured the stimulation of important effector mechanisms, which are key for the success of a vaccination," says Thomas Ebensen, who is working with Rimma Libanova on the new enhancer. Until now, the researchers were only able to show the effect in mice – but they think one step further: "With this new adjuvant, we want to improve already existing vaccines, such as those against influenza or hepatitis. Maybe it also helps to create new vaccines using component that in the past did not promote efficient immune responses using known adjuvants."

 

"The molecule might also help us to develop new vaccination strategies," says Professor Carlos A. Guzmán, head of the "Vaccinology and Applied Microbiology" Department at the HZI. His department is working on an alternative to the "shot": the snuff vaccination. Here, the vaccine is taken as a nasal spray to work where most pathogens enter the body: at the mucosae. Guzmán highlights, "c-di-IMP enhances also local mucosal immune responses, representing a strong candidate for the implementation of such type of vaccines. This is very important because mucosal vaccines can prevent not only diseases, but also to block infections before they even take place, thereby protecting also non vaccinated contacts against disease.”

 

Original article: Libanova R, Ebensen T, Schulze K, Bruhn D, Norder M, Yevsa T, Morr M, Guzman CA. The member of the cyclic di-nucleotide family bis-(3', 5')-cyclic dimeric inosine monophosphate exerts potent activity as mucosal adjuvant. Vaccine, Volume 28, Issue 10, 2 March 2010, Pages 2249-2258, ISSN 0264-410X, DOI: 10.1016/j.vaccine.2009.12.045.

 

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2010-03-23

Unexpected diversity of the nose

Scientists at the HZI explore the bacterial communities of the nose in order to prevent infection.

 

BiodegradationThe human body is colonized by bacteria. They live on our skin, in our body’s orifices and throughout our gastrointestinal tract. There they can prevent dangerous germs (pathogens) from colonising and thus protect us against such infections, or they help in digestion. When the immune system is weakened, even the so called harmless germs can become a problem and make us sick. One of these bacteria is Staphylococcus aureus. In almost one third of all people, S. aureus lives in the nose without causing any problems. However, it can be transmitted and be the cause of skin infections, muscular diseases or even life-threatening illnesses such as pneumonia or blood poisoning. Scientists from the Helmholtz Center for Infection Research (HZI) in Braunschweig together with doctors from the University Hospital Münster, have investigated if other bacteria could help in the fight against S. aureus. The scientists explored which bacteria occur in the nose and whether there are differences between carriers of S. aureus and people who do not have the germ. They found a wide range of different types of bacteria in the nose, including some types that appear dominantly in non-carriers. Their results are now published in the scientific journal "International Society for Microbial Ecology".

 

The human skin and mucous membranes are colonized by complex bacterial communities that protect us against infection, but occasionally they themselves can become a problem. "Little is known about how complex the composition of bacterial communities of the human body really is" said Dietmar Pieper, director of the Working Group on Microbial Interactions and Processes at the HZI. However, in order to fight infections such as those caused by S. aureus, it is important to understand how the bacteria interact and thus influence each other.

 

To examine the bacterial communities, the researchers at the HZI together with scientists at the University Hospital Münster analyzed the nasal swabs from 40 randomly selected individuals. The researchers were primarily interested in discovering which bacteria actually live in the nose. To find out, they used culture-independent methods that not only allow the precise examination of large numbers of samples, but also allow the detection of those bacteria that can not be grown or only grow poorly in the laboratory. They achieved this by analyzing a gene that occurs in all bacterial species and has the same function across all bacteria. However, certain regions of this gene differ from species to species and using these so-called variable regions the researchers were able to determine which bacterial species are present in the nose.

 

The findings were surprising. Of the many different species of bacteria inhabiting the nose, various species have not been described in humans before. In addition, the scientists found many species that can live without oxygen.
Subsequently, the researchers statistically determined that the bacteria can influence each other. The scientists found patterns where some bacterial species frequently occur together and where some bacterial species can not share the same habitat. "We were able to show that when species of the genus Finegoldia were present in the nose, S. aureus was typically absent" said Dietmar Pieper. The reason for this is yet to be elucidated. "This does not mean that S. aureus maybe cleared from the nose by Finegoldia, as this bacteria may also cause infection". The results highlight the importance of understanding how bacteria colonize and create habitats over the human body and also how they influence each other. From this work the researchers hope to develop future strategies to combat S. aureus infections.

 

 

Original article: Wos-Oxley ML, Plumeier O, von Eiff C, Taudien S, Platzer M, Vilchez-Vargas R, Becker K, Pieper DH. A poke into the diversity and associations within human anterior nare microbial communities. The ISME Journal advance online publication, doi:10.1038/ismej.2010.15

 

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2010-04-06

The immune system’s guard against cancer

Researchers from Helmholtz Center for Infection Research in Braunschweig, Germany have discovered how immuno-messenger substances can inhibit tumour growth

Galtte Muskelzellen (grün) in Kapillaren von Tumor-AdernThe human body has developed various mechanisms, through which it can protect itself against newly-developing cancer cells. For instance, killer-cells recognize and destroy altered cells in our organs every day. Once tumours have developed, they may be inhibited in growth by messenger substances from the immune system. Scientists from the research group “Molecular Immunology” at the Helmholtz Center for Infection Research (HZI) in Braunschweig have now succeeded to reveal a completely unexpected function of such an immunological messenger substance in the suppression of tumours; i.e., the molecule “beta-interferon” inhibits the tumour in its attempts to connect into the human blood circulatory system.  Moreover, it hinders the production of growth factors that support the formation of new blood vessels. The conclusion - the tumour cannot grow. The results from their study have been published in the latest issue of the scientific magazine "Journal of Clinical Investigation".

 

The connection with the blood circulatory system is a significant step in the development of cancer. Within the tissue where it is growing, the tumour develops an independent existence. With signal substances it entices white blood cells from the bone marrow into the tumour tissue. The task of these cells, usually, is to defend against infection and stimulate the healing of wounds. Within the tumour, these cells prompt new blood vessels to increase their rate of growth. Once the tumour is connected to the blood circulatory system, it is provided with nutrients for growth. It also can then disseminate its own cells  into the overall blood circulatory system as well and form metastases. Scientists at the HZI are now in the process of deciphering precisely how a messenger substance is able to inhibit this integration process into the blood circulatory system.

 

Messenger substances are the fine-tuning regulators of immune-cells; they activate or deactivate them, generate the production of growth factors or further messenger substances and initiate or terminate an immune reaction. One of these signal molecules is currently being used in therapy for several forms of cancer –interferon. How it works remains a mystery, so far, to scientists. The research scientist Jadwiga Jablonska from HZI has recently found a new mode of action against cancer beta-interferon a subtype of the interferons. The results surprised her: “Beta-interferon blocks the connection of the tumour into the blood vessel system by inhibiting immune cells to produce growth factors. This effect upon tumours was completely unexpected,” says Jadwiga Jablonska.

 

The research scientist allowed skin tumours to grow in two groups of mice; the first group of mice was not able to build beta-interferon, while the second group produced the messenger substance as usual within their bodies. After a few days, the research scientist investigated the growth rate of the tumour. “In mice that cannot produce beta-interferon, the tumours were considerably larger than in the animals that did have the signal molecule in their bodies.” With beta-interferon, the tumours not only grew slower – they formed fewer and smaller metastases as well.

 

The reason for the inferior rate of growth was found by the research scientist to be attributable to the lack of blood circulation within the tumours. “In the presence of beta-interferon, considerably fewer blood vessels developed within the tumour”, says Jadwiga Jablonska. The beta-interferon functioned through a small detour; it blocked the formation of vessel producing growth factors in cells that were enticed by the tumour to promote the connection with the blood-circulatory system. The research scientist discovered that the cells not only formed fewer growth factors, a smaller quantity of these cells found their way into the tumour, as well. “Only a negligible quantity of this messenger substance was sufficient to keep cells at bay and to inhibit growth factors, thus arresting the growth of tumours”, says Jadwiga Jablonska.

 

“This mode of action on the part of beta-interferon had previously been unidentified”, says Siegfried Weiss, leader of the working group “Molecular Immunology” at HZI.  The messenger substance actually plays a significant role in viral diseases and reactions to infections. “We now are attempting to understand how the network of tumour, immune cells and messenger substance functions, in order to discover new target structures for cancer therapy”, says Weiss.

Original article: Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest. 2010 Apr 1. DOI: 10.1172/JCI37223

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2010-04-15

Improving the degradation of toxic hydrocarbons

Initiation of a world-wide research project under the direction of the HZI

Das italienische Forschungsschiff &quot; R/V/Urania&quot; des CNRHelmholtz Centre for Infection ResearchBraunschweig, Germany 15 April 2010 – The world-wide project “MAGICPAH”, coordinated by the Braunschweiger Helmholtz-Zentrum für Infektionsforschung (Helmholtz Center for Infection Research in Braunschweig- HZI), is examining how bacterial communities are able to support the degradation of toxic polycyclic aromatic hydrocarbons. “MAGICPAH” is a collaboration of thirteen partners from nine countries. Research institutions and industrial enterprises have initiated the project today at the HZI. The significance of this project is reflected in the gravity of the cargo ship disaster on the Australian “Great Barrier Reef”. The reef was threatened in April 2010 by four tonnes of heavy oil that escaped from the tanker.

 

Hydrocarbons chemicals that consist only of the elements carbon and hydrogen.  They play a very important role world-wide as fossil fuels. An especially significant sub-group are the so-called “polycyclic aromatic hydrocarbons” (PAH).  These poorly degradable, often toxic and carcinogenic hydrocarbons are responsible for, among others, the contamination of soils. They can be found in crude oil and in high abundance in heavy oil; they are thus readily capable of endangering marine environments.

 

The partners of “MAGICPAH” have initiated their collaboration today in the from of a kick-off meeting at the HZI under the coordination of Dietmar Pieper, head of the research group “Microbial Interactions and Processes”.

 

The primary goal of the research project is to explore, understand and exploit the degradative capabilities of bacteria in soil and in marine environments. “Petroleum degrading bacterial communities, harbour a considerable and hitherto unexploited potential”, says Dietmar Pieper.

 

The project is intended to initially analyze microbial diversity and the molecular processes, which play a significant role in the removal of PAH contaminants from soils, sediments and waste waters. This however already causes problems as the majority of bacteria in soils or marine ecosystems cannot be cultivated. “This hitherto unutilized diversity of microbial activities can only be visualized by means of so-called cultivation-independent methods”, says Dietmar Pieper. These cultivation-independent methods make use of the micro-organisms’ capabilities without having to previously propagate them in the laboratory. “The information collected here in different experimental systems will be used for the design of new knowledge-based strategies for the mitigation of ecological damage caused by polycyclic aromatic hydrocarbons (PAHs) in various habitats. Furthermore, our methods enable direct access to new metabolic reactions that can be used for industrially relevant products”, concludes Dietmar Pieper.

 

The EU is funding the project with three million euros over the next four years. In addition to the HZI, the partners from industry originate in Italy and the Czech Republic, while the partners from the research centres originate in Italy, Spain, Great Britain, Germany, Denmark, France, Colombia and Canada.

 

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2010-05-14

Helmholtz Centre for Infection Research receives project funding from the Bill und Melinda Gates Foundation

Innovative nanoparticles release vaccine through perspiration

 

 Gates-StiftungThe Helmholtz Centre for Infection Research (HZI) has received a grant through the current round of the funding programme “Grand Challenges Explorations” of the Bill & Melinda Gates Foundation. The programme is supporting a global health project for development of nanoparticles that release the vaccine active ingredients through the skin upon contact with perspiration. The Braunschweig Helmholtz Centre for Infection Research (HZI) is implementing the research project POLMITRANSVAC (Pollen Mimetic Transcutaneous Vaccination) in cooperation with the Helmholtz Institute for Pharmaceutical Research Saarbrücken (HIPS). Successful projects have the opportunity to receive a follow-on grant of up to $1 million US in a second phase.

 

“We are linking for the first time our expertise at the HZI in the development of vaccines with multi-year experience regarding the formulation of active ingredients in nanoparticles, which the scientists at HIPS in Saarbrücken have available”, say the scientists Carlos Alberto Guzmán from the HZI, Claus-Michael Lehr and Steffi Hansen from HIPS, as well as Ulrich Schäfer from the Saarland University.

 

“The novel concept in our method is the pathway through which the vaccine is administered. The nanoparticles penetrate via the hair follicles into the skin, then come into contact with human perspiration and release the active vaccine ingredients, mimicking what normally occurs during pollen sensitization. This method of vaccination by-passes the traditional and more painful needle-based vaccines and has the potential to stimulate mucosal immune responses.

 

The research project of the Helmholtz Centre for Infection Research is one of 78 research projects which are being funded by the Gates Foundation in the fourth round of “Grand Challenges Explorations”. The initiative is intended to support worldwide researchers and strategies for diagnosis and avoidance of infectious diseases, and to develop improvements in family health. The selection process took into consideration 2,700 applications that had been submitted. Overall, the Foundation research projects support 19 countries on six continents.

 

“Grand Challenges Explorations continues to generate unique and creative ideas aimed at tackling global health issues” explained Tachi Yamada, president of the World Health Programme of the Gates Foundation. “We are convinced that a few of these ideas can and will lead to new innovations and ultimately to new solutions that will save lives.”

 

 

 

About Grand Challenges Explorations

Grand Challenges Explorations is a five-year initiative endowed with more than $100 million US, which funds innovations in the area of world health. It is a part of the “Grand Challenges in Global Health” Initiative, which is supported by the Bill and Melinda Gates Foundation in order to facilitate important improvements in global health matters. Grand Challenges Exploration is still accepting applications until 19 May 2010 for the next round. The complete explanation of requirements for the application, including the list of thematic areas for which applications are currently being accepted, can be found at the website.

 

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2010-05-25

New pathway to cheap Insulin

Researchers from Helmholtz Centre in Braunschweig, Germany publish new and more efficient method to manufacture insulin.

 FermenterAnzucht von Säugerzellen im Fermenter, (Dr. Volker Jäger); Fotograf: Bierstedt; Foto: GBFMore than eight million diabetics live in Germany. Diabetes is not restricted to our prosperous society and the highest growth rates often occur in countries with aspiring economies such as in Asia. Worldwide, more than 285 million people suffer from this illness; with 50 million diabetics, India is the country with the most people affected by this disease. In Europe, Germany shows the highest prevalence in the population with twelve percent. In a German-Indo collaboration, researchers from the Helmholtz-Centre for Infection Research (HZI) in Braunschweig, Germany have now developed a new method to cheaply produce insulin for the treatment of diabetes. The group’s results have now been published in the open access online research magazine “Microbial Cell Factories”. With this, all information is freely accessible for everyone and is not subject to patent law.

 

As we did last year with an alternative protocol for the development of a hepatitis B vaccine, we again decided to use this way and make our knowledge available for everybody,” says Ursula Rinas from the HZI, who chairs the German side of the project. Thus, people can access “insider-information” that makes it possible to cheaply produce medicine which in return can be affordable to people in developing countries.

 

The researchers wanted to develop a new procedure to increase the yield of an insulin precursor from which the actual insulin can be obtained, and in this way reduce costs. They found the yeast Pichia pastoris and modified the cells so that they produce the building block for insulin while growing on a special medium. The results were highly gratifying: “With our procedure, Pichia pastoris delivers high yields – twice as much as known before”, says Ursula Rinas. “Already with few cells it is possible to produce a lot of the insulin precursor.”

 

In the early 1980s, insulin was the first recombinant product approved by the FDA for human application. Today, human insulin is produced as recombinant protein, using two major routes. One route involves the production of the insulin precursor using the bacterium Escherichia coli as expression host with complex subsequent isolation, solubilization and refolding procedures. The other route involves the well-known baker’s yeast Saccharomyces cerevisiae. The advantage of the latter route lies in the secretion of a soluble insulin precursor into the culture supernatant, making it easier for isolation and chemical modification. The newly described method from Ursula Rinas and her group also uses this route. The isolation of the precursor from the culture supernatant is only followed by enzymatic finishing. Insulin produced with this new method can be used normally and is identical to human insulin. Currently, the researchers are working on a method to produce a vaccine against dengue fever using the same system as described here.

 

For most people in developing countries medicine is too expensive. The purchasing of insulin in those countries is often cost prohibitive. Another problem is patent law that makes it impossible to recreate medicine and sell it at low prices. Once a patent has expired, as is the case with insulin, the so called generic drugs can be produced cheaply. Unfortunately, emerging nations very often lack the insider knowledge to produce those generics.

 

 

Originalartikel: Application of simple fed-batch technique to high-level secretory production of insulin precursor using Pichia pastoris with subsequent purification and conversion to human insulin. Gurramkonda C, Polez S, Skoko N, Adnan A, Gabel T, Chugh D, Swaminathan S, Khanna N, Tisminetzky S, Rinas U. Microb Cell Fact. 2010 May 12;9(1):31. [Epub ahead of print]

 

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2010-06-07

The right response to every pathogen

Researchers from Helmholtz-Centre in Braunschweig, Germany, decipher how mast cells set immune defence on the right track.

Mastzellen KLEINIn the event of an infection, the immune system releases messenger substances. These molecules can either activate immune cells to defeat invading pathogens, or inhibit them to prevent an excessive immune reaction. For this, the immune system has to decide very quickly what mixture of activating and inhibiting messenger molecules leads to a successful defence. Researchers from the Helmholtz-Centre for Infection Research in Braunschweig, Germany, have now been able to show that hitherto underrated immune cells, so-called mast cells, decide at a very early stage of an infection which way the defence has to go. They only produce the crucial messenger substance beta-interferon during a viral infection, not during a bacterial infection. The reason for this: While on the one hand the molecule always helps to defeat viruses, it hinders on the other hand important immune cells to kill bacteria – and thus impairs the defence. The group’s results have now been published in the scientific magazine “PNAS”.

 

Mast cells play a central role during allergic reactions, a function researchers have concentrated on until now. They reside directly under the skin and mucosae, and react immediately when an allergenic substance enters the body. As a result, reddened mucosae, swelling, runny eyes and a runny nose occur. However, mast cells also seem to have a crucial, but only superficially understood, function during pathogenic defence. “They wait precisesly at that position where pathogens enter the body,” says Nelson O. Gekara, researcher in the group “Molecular Immunology” at the HZI, “and thus belong to the very first line of immune defence.”

 

To investigate how mast cells react when they come in contact with bacteria and viruses, the HZI-researchers incubated mast cells and pathogens together in a petri dish. Then, they measured what messenger substances the cells produced. As soon as a virus infection occurred, the scientists were then able to detect beta-interferon, produced by the mast cells.  Conversely, during a bacterial infection, no beta-interferon was found. “Until now it has been unknown that mast cells can virtually decide whether they produce beta-interferon or not,” says Nicole Dietrich who did research on the mast cells. “During a viral infection, beta-interferon helps because it activates mechanisms in surrounding cells that support the virus defence.”

 

The researchers found the reason for why mast cells do not produce beta-interferon during bacterial infections in the defence line that follows mast cells: “Beta-interferon inhibits precisely those cells that quickly eliminate invading bacteria,” says Nicole Dietrich. Thus, mast cells determine very early which direction the immune defence is taking.

 

Important for this decision making are receptors on the surface of all immune cells: So-called “Toll-like receptors” activate mast cells as soon as a pathogen enters the body. When the receptors are triggered, mast cells produce a number of messenger substances that attract cells or keep them at distance, activate or inhibit them and thus regulate an optimised immune response.
“To produce beta-interferon, immune cells have to absorb the receptors and transport them into the cell interior. During a bacterial infection, mast cells refuse to incorporate the receptor and thus do not produce beta-interferon”, says Nelson O. Gekara. This is another step towards understanding the complex network of messenger substances, immune cell and pathogen defence. “It seems as if every line of defence can precisely decide which step will be the next and best.”

 

Original article: Dietrich Nicole; Rohde Manfred; Geffers Robert; Kröger Andrea; Hauser Hansjörg; Weiss Siegfried; Gekara Nelson O. Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proceedings of the National Academy of Sciences of the United States of America 2010;107(19):8748-53.

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2010-07-05

A new opportunity for hepatitis C research

Scientists at TWINCORE develop new model approaches for HCV research.

Infizierte humane Zellen anfangThe hepatitis C virus is highly specialised. We humans are its natural hosts. The only other living organisms that could be infected with the hepatitis C virus in the lab are chimpanzees. Nevertheless it is – from the viewpoint of the virus – highly successful: around 170 million people are chronically infected with the virus. And with the chronic infection the risk of developing liver cancer also increases.

 

Researchers worldwide are working to develop vaccines and medication to combat the virus. The problem is that although they are able to research in liver cell cultures, when they want to find out how the immune system controls an infection or whether possible vaccines are effective research comes up against a brick wall: tests at such an early stage are unthinkable for humans or chimpanzees. At TWINCORE researchers are now adapting the HCV to mice, thus enabling immunologists and vaccine researchers to take the next steps against this illness in the future. Because the immune system of mice is very similar to that of humans and it is only when vaccines are successful and safe in animal experiments that researchers can take the risk of transferring them to humans.

 

The fact that HCV can only infect humans and chimpanzees is partly down to the highly complicated mechanism with which it accesses the cell. The virus has to first bind four different molecules on the surface of our liver cells. This triggers a mechanism in our cells that transports the virus into the liver cells. "Mice also have these receptors on their liver cells in principle," says scientist Julia Bitzegeio of the Department of Experimental Virology at TWINCORE, "however, they do not fit those on the surface of the virus."

 

The two molecules that cause particular difficulty are called CD81 and occludin – these need to be human, otherwise the virus has no chance of infecting the cell. To make the HCV "mouse-capable" the researchers resorted to a trick: they have removed the CD81 receptor from human liver cells and replaced it with mouse CD81. In an electrical field they then tore tiny holes in the cell membrane before inserting the HC virus artificially through these holes. "The virus reproduced inside the cells and we repeatedly inserted the virus into the altered liver cells," explains Julia Bitzegeio. This led to the highly transformable virus gradually changing   until it was able to penetrate the cells with mouse CD81 receptor even without assistance.

 

"In this selection process the surface of the virus altered so much that it continued to infect human cells very quickly, but also simple mouse cells containing the four mouse variants of the HCV receptors," says Research Group Leader Professor Thomas Pietschmann. The mouse-adapted virus is able to penetrate the mouse cells; however, the human specialisation of the HC virus is so high that it is unable to reproduce in the cells. "Successful infiltration is the first step towards a new small animal model, one that is urgently required for immunological investigations and the development of vaccines against HCV."

 

TWINCORE is an joint venture between Helmholtz-Center for Infection Research at Braunschweig an the Hannover Medical School.

 

Literature: Bitzegeio J, Bankwitz D, Hueging K, Haid S, Brohm C, et al. (2010) Adaptation of Hepatitis C Virus to Mouse CD81 Permits Infection of Mouse Cells in the Absence of Human Entry Factors. PLoS Pathog 6(7): e1000978. doi:10.1371/journal.ppat.1000978

 


Further information: www.twincore.de

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2010-08-17

Helmholtz Centre for Infection Research mourns Scientific Director

Professor Jürgen Wehland dies unexpectedly

Prof. Dr. Jürgen WehlandProf. Dr. Jürgen Wehland, wissenschaftlicher Geschäftsführer des Helmholtz-Zentrums für InfektionsforschungBraunschweig, August 18, 2010 – The Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany is mourning the loss of its Scientific Director, Professor Jürgen Wehland, PhD. On August 16, 2010, Jürgen Wehland died unexpectedly during a vacation in Sweden. “We express our deepest condolences to his family and friends,” says Ulf Richter, Administrative Director of the HZI. “His death is a great loss for every employee at the Helmholtz Centre and in the Helmholtz Association. We have lost an outstanding scientist and for many of us a longtime friend.”

 

„Professor Wehland was a highly respected scientist and a universally appreciated colleague,” says Professor Jürgen Mlynek, President of the Helmholtz Association of German Research Centres in Berlin. “In our thoughts we are with all the people that were close to Jürgen Wehland, both personally and professionally.”

 

Professor Wehland studied biology at the Göttingen University and took his Diploma and PhD thesis at the Max Planck Institute for Biophysical Chemistry in Göttingen. After his doctorate in cell biology at the Bonn University, he went to the National Cancer Institute in Bethesda, USA for postdoctoral studies. In 1989 he came as junior scientist to the Society for Biotechnological Research (GBF, now the Helmholtz Centre for Infection Research) in Braunschweig to work in the Division of Microbiology. From 1994 to 1997 he was Head of the Division of Cell Biology. In 1997 Jürgen Wehland was appointed University Professor in Cell Biology and Immunology at the Technical University Braunschweig and Head of the Department of Cell and Immune Biology at the GBFAfter an interim period starting in September 2009, Jürgen Wehland was appointed Scientific Head of the Helmholtz Centre for Infection Research in January of this year.

 

Jürgen Wehland was Vice President of the German Society for Cell Biology and obtained the Descartes Prize for his research on Listeria bacteria as pathogens in 2007. His more than 160 publications on processes of the cell skeleton and on Listeria were published in a number of high-ranking scientific journals. Jürgen Wehland takes a lot of credit that today’s HZI is a modern and high-performance centre for infection research.

 

Furthermore, Jürgen Wehland was member in several executive boards and committees such as the German Special Research Field of the German Research Society, member of the Expert Advisory Committee of the Max Planck Institute for Infection Biology in Berlin and Chairman of the Senate Panel “Evaluation” of the Leibniz Association.

 

Professor Dr. Jürgen Wehland died at the age of 58. He is survived by his wife and his two grown-up daughters.

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2010-10-05

Mice with human body’s defences

New method will simplify study and treatment of diseases

 Kommunizierende ImmunzellenMice with human body’s defences 0B New method will simplify study and treatment of diseases Therapeutic antibodies can be an efficient alternative when common drugs do not work anymore.  However, antibodies obtained from blood of animals such as mice could not be used: The human immune system recognizes them as foreign and rejects them. In an international cooperation, scientists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, the Academic Medical Center of the University of Amsterdam (AMC-UvA) and AIMM Therapeutics, Amsterdam, The Netherlands, the Pasteur Institute, Paris, France and Hannover Medical School, Germany have now succeeded in developing a promising approach to solve this problem. In this joint effort funded by the Bill and Melinda Gates foundation, scientists led by Prof. Carlos A. Guzmán (HZI), Prof. Hergen Spits (AMC-UvA), Dr. Tim Beaumont (AIMM) and Prof. James P. Di Santo (Pasteur) developed an approach where; with the help of human stem cells they generate mice with a human immune system, which were then vaccinated to produce human monoclonal antibodies. These fully human antibodies could help in the research and therapy of human diseases. Their results have now been published in the current online issue of the scientific journal “PLoSOne”.    

 

Antibodies are small proteins, produced by B cells during an immune response. They bind at and thus mark invading pathogens so that scavenger cells recognize and destroy them. “The task of our immune system is to distinguish between self and non-self structures,” says Professor Carlos A. Guzmán, head of the department of “Vaccinology and Applied Microbiology” at the HZI. “This means also that only human antibodies come into question for an antibody therapy”, since the human immune system fights antibodies from mice – a threat for the patient. Furthermore, it is cumbersome to humanize murine antibodies for human treatment or to generate human B cell clones producing high quantities of antibodies.  

 

The scientists used an already established method to give a human immune system to mice, which were then exploited to solve this problem: they injected human stem cells into young mice that due to a genetic defect lack an immune system. The stem cells migrate into the bone marrow, proliferate, differentiate and lead to the generation of a human immune system. “In our in-depth investigations we were able to detect all import types of immune cells in these mice,” says Dr. Pablo Becker, scientist in the HZI department “Vaccinology and Applied Microbiology”.  

 

To validate the new approach, mice with a human immune system were vaccinated against Hepatitis B or Tetanus. The scientists then isolated human antibody producing B cells from the mice and treated them so that they survive outside the body in a cell culture dish and continue producing antibodies. Then, the researchers took a deeper look at the antibodies. The results give hope: “Antibodies from mice with a human immune system showed good properties in our tests, but the model still need to be improved for broad implementation in biomedicine,” says Pablo Becker. “However, we were able to demonstrate for the first time that it is possible to produce human monoclonal antibodies using humanized mice.” Now it is important to improve this mouse model to use it one day for the development of advanced therapies against human diseases. “In the future this approach might represent the most powerful tool to develop therapeutic antibodies for clinical use,” hopes Becker.

 

Original Article: Becker PD, Legrand N, van Geelen CMM, Noerder M, Huntington ND, et al. 2010. Generation of Human Antigen-Specific Monoclonal IgM Antibodies Using Vaccinated “Human Immune System” Mice. PLoS ONE 5(10): e13137. doi:10.1371/journal.pone.0013137

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2010-11-15

Casting show within the lymph nodes

Computer models and experiments reveal that seemingly random movements of the cells within lymph nodes facilitate optimization of the immune response.

Teaserbild PM Meyer-HermannLymph nodes are the market place for the immune system; cells exchange information regarding invading pathogens here and prepare an appropriate immune response. What appears from the outside to be meaningless and chaotic teeming of millions of cells is actually a flight-path that is highly coordinated and targeted. Researchers from the Helmholtz Centre for Infection Research (HZI) in Braunschweig have recently generated a mathematical model for the movement of immune cells in lymph nodes and were able to use this to explain the results of experiments by international co-operation partners at the Rockefeller University in New York, USA and the New York School of Medicine. Their findings: immune cells go through an optimization cycle during their to-and-fro movements, and at the end of many of these cycle the appropriate immune response to the respectively invading pathogen emerges. These results have been published in a recent issue of the scientific magazine “Cell”.  

 

Ordered chaos within the lymph nodes
So-called germinal centres, within the lymph nodes in which defence cells mature, play a key role during the immune response. They were first described in the 19th century and are spatially divided into a light zone and a dark zone. However, it is nonetheless still not completely understood what happens in these two zones and what role the movements of the immune cells play.  

 

When one typically observes the cells through a microscope, they give the impression that their movements are spontaneous and random. “The apparent chaos in the lymph nodes is actually considerably ordered”, says Michael Meyer-Hermann, Director of the “Systems Immunology” Department. Whether there is a system inherent in the motions of these cells, is a topic that has in the past generated much controversy among scientists. The astounding results from these recent studies however give a clear indication; the exchange of information within the lymph nodes is based on structured movement of the cells, which move back and forth between the two spatially separated zones. During this process, round for round, only those defence cells are selected that are most suited to the respective germ, in order to subsequently make available the optimal weapon to the organism – effective antibodies.  

 

“It is a continuously-repeating cycle of mutations in the dark zone, and a selection of good cells in the light zone”, says Michael Meyer-Hermann. “The immune cells propagate, mutate and slightly change their antibodies in the process. The immune system then evaluates whether these mutations can deliver an improved immune defence – if this is the case, it selects the corresponding cells. Then the cycle begins again. Consequently we have the production of optimized antibodies that are able to efficiently bond with the respective pathogens, thereby marking them for scavenger cells.” 

                           

New methods make it possible to track individual cells
In order to be able to examine what pathway individual cells follow through the lymph nodes, American researchers from the New York Rockefeller University and the New York School of Medicine in the USA developed a novel method for representation; the researchers introduced a gene into the genetic information of mice that provides the immune cells with a dye. The unique thing about this particular dye is its capacity to illuminate only when it is activated by a beam of light with a specific wave length. When the researchers want to examine a cell, they activate the dye, causing the cell to illuminate which allows scientists to track it on its pathway through the lymph node.      

 

This highly targeted movement was only able to be disclosed with the aid of the new measuring system together with mathematical modelling of the transitional frequency of occurrence between the zones. “Our analysis of cell movement clearly substantiates the significant role that mathematics plays in biology today”, explains Michael Meyer-Hermann. “In order to solve important scientific problems, predictions are derived from the mathematical models; these predictions then serve as the basis for new experiments, while making data comprehensible.”       The new findings regarding selection of immune cells and optimization of an immune response could provide significant help, according to Michael Meyer-Hermann, in the improvement of future vaccinations for which the formation of effective antibodies within the human body plays an important role. 

 

Original article: Germinal Center Dynamics Revealed by Multiphoton Microscopy with a Photoactivatable Fluorescent Reporter. Gabriel D. Victora, Tanja A. Schwickert, David R. Fooksman, Alice O. Kamphorst, Michael Meyer-Hermann, Michael L. Dustin and Michel C. Nussenzweig. Cell, Volume 143, Issue 4, 592-605, 12 November 2010. doi:10.1016/j.cell.2010.10.032  

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2011-01-07

Tracking down infections with super-microscopes

Green light for the new “Centre for Structural Systems Biology”

Fahnen HZI
 Ansicht vom HZI mit Fahnen im Vordergrund Fahnen HZI Ansicht vom HZI mit Fahnen im VordergrundInfection researchers and physicists in northern Germany are joining together in the hunt for pathogens: under scientific co-ordination of the Braunschweiger Helmholtz Centre for Infection Research (HZI), the new “Centre for Structural Systems Biology” (CSSB) is emerging on the campus of the Deutsche Elektron Synchrotron (DESY) in Hamburg-Bahrenfeld. This inter-disciplinary centre with partners from various universities and research facilities from Lower-Saxony, Hamburg and Schleswig-Holstein is focusing on the goal of tracking down attacks by germs- and this with atomic precision. At DESY in Hamburg, the Federal Minister for Education and Research,  Professor Annette Schavan, together with the Hamburg Senator for Science, Dr. Herlind Gundelach, and the Lower-Saxony Minister for Science and Culture, Professor Johanna Wanka, signed the Federal-State agreement for construction of the CSSB. A total of 50 M. euros is being made available for this project.  

 

“Infection research in northern Germany already has an excellent reputation”, said Professor Dirk Heinz, Acting Scientific Managing Director of the HZI. “We are now making use of the synergies from various research fields in a much better way. The CSSB – like a lighthouse – is going to make our research efforts more visible at both the national and international levels.”  

 

“Our light sources are world-class and offer optimal conditions for structural biology. With the aid of super-microscopes such as PETRA III and FLASH, the molecular basis for diseases can be analyzed with extremely high spatial and temporal resolution”, emphasizes the Chairman for the DESY governing body, Professor Helmut Dosch.  

 

Pathogens are miniscule; nevertheless they generate considerable repercussions for human beings. Even smaller are the tools with which these pathogens are able to infect us; the interplay of molecules upon their surfaces enables them to gain access into our bodies. Structural biologists are deciphering these interactions at the atomic level and examining precisely how molecules and proteins are constructed. In this manner, researchers are able to reveal much more than just the process of reciprocal effects between pathogens and their hosts. They can also find points of application for new active ingredients, anti-infectives and vaccines.   System biologists, on the other hand, are examining biological systems such as cells or pathogens in their totality: Which processes are simultaneously taking place within an organism at a specific point in time? They collect and assess huge quantities of data regarding metabolism processes as well as interactions between proteins.  

 

The CSSB is creating a bridge between structural biology and system biology; this is the place where biologists, chemists, physicians, physicists and engineers are jointly evaluating the interactions between pathogens and their hosts. In this regard, DESY is able to make available to them, unique in Germany, the following: PETRA III, the world’s most brilliant storage-ring-based X-ray source, and FLASH, the world’s first-ever X-ray free-electron laser in the vacuum ultraviolet and in the soft X-ray region.  Additionally, the European XFEL, a first-class X-ray laser, is currently being built and the “Center for Free-Electron Laser Science” (CFEL) will be erected on the DESY campus as well. These light sources, based on particle accelerators, produce intensive shortwave rays (radiation?) with special characteristics. On this basis, researchers can examine biological samples in various styles – from the structural analysis of individual molecules to real-time representation of the functions within living cells.  

 

In light of inter-disciplinary co-operation in the new CSSB research facility, it will be much easier to use the highly-modern radiation sources at DESY for biological issues. In this manner, departments from university and non-university research facilities work together at DESY in close collaboration in order to examine and better understand, with the aid of system biology, complex cellular functions with the “super microscopes”.   Planning for the construction is slated to commence immediately after the signing of the contract; construction is planned for the year 2012.

Partners in the Centre for Structural Systems Biology:

 

 

Hamburg:


Universität Hamburg, Fakultät für Mathematik, Informatik und Naturwissenschaften
Universitätsklinikum Eppendorf, Hamburg
Deutsches Elektronen-Synchrotron DESY
Heinrich-Pette Institut für Experimentelle Virologie und Immunologie, Hamburg
Bernhard-Nocht-Institut für Tropenmedizin, Hamburg 

 

 

Lower-Saxony:


Helmholtz-Zentrum für Infektionsforschung, Braunschweig
Medizinische Hochschule Hannover

 

 

Schleswig-Holstein:


Universität zu Lübeck
Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften

 

 

National and international Partners:


European Molecular Biology Laboratory EMBL
Forschungszentrum Jülich

 

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2011-02-21

The hunt for deadly pathogens

3 March, 2011: International experts meet for ”Day on Deadly Killers“ at HZI

HZI 0610 fahnen hzi hg 001 kleinThe causes of dreaded diseases such as Cholera, Anthrax, Rabies and AIDS are the main focus of a symposium at the German Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI). International scientists from all over the world will meet on the 3rd of March, 2011 to talk about the current state of infection research at the “Day on Deadly Killers”. Experts from Europe, the US and Asia will present their research results and discuss how new therapeutical approaches against infectious diseases may look like.  

 

Amongst the invited guests are the renowned US scientist Dr. Henry F. Chambers, MD from General Hospital in San Francisco and the Dutch researcher Professor Albert D.M.E. Osterhaus from the University of Rotterdam. Henry Chambers is a specialist for antibiotic-resistant hospital pathogens, whereas Albert Osterhaus is known worldwide for his research on Influenza viruses.   The “Day on Deadly Killers” starts at 2:00 p.m. in the Forum building on the HZI campus and ends at around 7:30 p.m.  

 

“We are very happy to welcome well-known and established experts of infectious diseases at the HZI to this event,” says Dr. Sabine Kirchhoff, coordinator of the HZI Graduate Schools that host the symposium. For the PhD students, the contact and exchange of ideas with international researchers is very important. “We are keen to ensure that young scientists look beyond the horizon of their own research and build up international networks already at the very beginning of their career.”   Infectious diseases cause a quarter of all fatalities worldwide and are a serious global health concern. Additionally, growing resistances against antibiotics, the lack of therapies and a declining willingness to vaccinations make it difficult to fight pathogens.  

 

The symposium is open for everybody who is interested in listening to and discussing about different aspects of infection research with a scientific audience. All talks will be held in English. We kindly ask for a registration. There, you also find the programme for the event. Participation is free of charge.  

 

The symposium is held on the behalf of the international PhD programme “HZI Graduate School”, a joint PhD school of the HZI, the Hannover Medical School, the Technical University Braunschweig and the Veterinary School Hannover. The lecture series with renowned experts talking about their infection research takes place at the HZI for the seventh time now.

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2011-03-11

Full Throttle on the DNA

How the immune system controls itself: HZI scientists clarify the mechanism

 

T_ZellenMillions of Germans suffer from autoimmune diseases such as rheumatism, diabetes or chronic intestinal inflammation: the body’s defence system raises a false alarm and starts to attack its own body cells. The reasons for such overreactions are diverse and have not been understood completely until now. Therapies can only cure the symptoms. In collaboration with the Charité in Berlin and the company Epiontis, scientists from the German Helmholtz Centre for Infection Research in Braunschweig (Helmholtz-Zentrum für Infektionsforschung, HZI) have now found that the molecule CCR6, which is located on the surface of immune cells and is responsible for directing them to their site of action, is only produced as required. The responsible gene is activated by removing a chemical tag that usually silences the gene. The results add a new piece to the puzzle of understanding autoimmune diseases and will be of interest for new therapy concepts. The scientific magazine “Blood” has now published the results in its current issue.

 

Cells communicate with chemical substances that bind receptors on the cell’s surface. They can trigger various reactions. The receptor CCR6 for example is responsible for guiding T cells – a special kind of immune cell – to places of inflammation.

 

The HZI researchers have now discovered that certain regions on the DNA for the CCR6 gene are chemically modified: when the DNA is tagged with methyl groups, no CCR6 is produced. On the other hand, when the DNA is free of these groups, CCR6 is always present on the cell surface. When an immune cell receives an appropriate signal, it releases the tag from the genes and they become activated.

 

The cycle of methylation and demethylation is a well-known chemical modification of the DNA, resulting in an inactivation and re-activation of certain gene regions. However, the sequence of the four base pairs in the DNA is not changed but the activity of the affected DNA region is controlled.

 

“Removing the methyl groups from the DNA functions as a turbo: The cell starts to constantly express CCR6”, says Dr. Stefan Flöß who performed the experiments at the HZI in Braunschweig. In the case the immune system selects the wrong cell to express CCR6, it may have fatal consequences for the immune system and the body. “In autoimmune diseases, the equilibrium of cells enhancing inflammation and those relieving inflammation is disturbed.  In such situations dysregulation of CCR6 may play a crucial role”.

 

“The knowledge of the mechanism of CCR6 regulation may help in the future to improve diagnostics of autoimmune diseases”, says Flöß. “You may be able to check the blood of patients if the presence or absence of CCR6 on the cells’ surfaces correlates with the progress of the disease.” 

 

 

Publication: Steinfelder S, Floess S, Engelbert D, Haeringer B, Baron U, Rivino L, Steckel B, Gruetzkau A, Olek S, Geginat J, Huehn J, Hamann A., Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells. Blood, 10 March 2011, Vol. 117, No. 10, pp. 2839-2846.

 

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2011-03-31

A better understanding of the ageing immune system

German Research Network wants to optimize therapies for elder people.

 

bmbf logoOur society gets older, people live longer. The price we pay: infectious diseases can easier overcome the immune system. Like all organs, the immune system does not function flawlessly in old age. A new collaboration of university and non-university research institutes and two companies is investigating why our immune defence is getting weaker when we become old. The project “GERONTOSHIELD”, funded by the German Federal Ministry of Education and Research (BMBF), now received a 2.6 Million Euro funding for the next three years. “GERONTOSHIELD” is part of the BMBF programme “Systems biology for a better health in old age – GerontoSys2” that promotes systems biological approaches to find out the cellular and molecular mechanisms responsible for ageing. The kick off meeting of the new research network took place at the German Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, on March 31st and April 1st, 2011.

 

A better understanding and new approaches to optimize therapies for the elderly in the future is the goal of the scientific partners. The scientific coordination is located at the department of “Vaccinology and Applied Microbiology”, headed by Professor Carlos A. Guzmán, at the HZI in Braunschweig.

 

The immune system has to deal with a loss of cells in old age. Furthermore, the remaining cells react less efficiently to infections or vaccinations. Finally, most drugs are optimized for young adults. “Every tenth person over 65 dies due to the flue,” says project coordinator Professor Carlos A. Guzmán. “We still know too little about which changes occur in an ageing immune system.” Thus, it is necessary to optimize existing therapies and to develop new approaches to treat diseases in the elderly, says Guzmán.

 

Here, adjuvants play an important role, chemical compounds that boost the immune system and improve the efficiency of a vaccination. Guzmán and his group want to understand how young and old immune systems react to those adjuvants. “In the end, this knowledge would help to develop new vaccination strategies that are specifically tailored to old people,” says Guzmán. 

 

“GERONTOSHIELD” seeks the holistic understanding of these processes at the meeting point of two disciplines: biology and mathematics. On the one hand, researchers investigate how immune responses in young and old mice differ from each other. The results are then transferred onto human cells. Finally, systems biologists generate mathematical models from these data. With these tools, the researchers would like to comprehend what happens in an old organism to identify the underlying mechanisms responsible for altered responses in the elderly. This would enable the development of personalized strategies for the aging population. 

 

“We also seek to identify risk markers predicting increased susceptibility for infectious diseases in the elderly,” says Professor Michael Meyer-Hermann, head of the department “Systems Immunology” and co-coordinator of the project. These markers would allow detecting individuals or patients with a high risk for severe disease, thereby enabling to earmark them for specifically tailored therapies for this high risk group, says Meyer-Hermann.

 

Both researchers are convinced that “GERONTOSHIELD” can significantly contribute to better understand the processes in the ageing immune system and thus be a benefit for the medical care of elderly people in the future.&nb

Informationen about the BMBF project:

GERONTOSHIELD is part of the programme “Systems biology for a better health in old age” by the German Federal Ministry for Education and Research (Bundesministerium für Bildung und Forschung, BMBF). The BMBF is funding the projects “GerontoSys” and “GerontoSys2” to promote research on cellular and molecular processes during ageing. Furthermore, promoting junior researchers in the field of systems biological research in ageing is an important goal. For more information please visit the German site. 

 

The Partners:

1. Helmholtz-Zentrum für Infektionsforschung GmbH, Braunschweig

Professor Dr. Dr. Carlos A. Guzmán, (Coordinator)
Department of Vaccinology and applied Microbiology

Prof. Dr. Michael Meyer-Hermann (Co-Coordinator)
Department of Systems Immunology

Dr. Thomas Ebensen
Department of Vaccinology and applied Microbiology

2. University Tübingen

Prof. Dr. Graham Pawelec
Ageing & Tumour Immunology group, Section Transplantation Immunologie / Immune Hematology, Medizinische Klinik II

 

 

3. Friedrich-Schiller-University Jena 

Prof. Dr. Stefan Schuster
Department for Bioinformatics, Faculty for Biology and Pharmacy

 

 

4.  University and University Hospital Regensburg 

Prof. Dr. Rainer H. Straub
Department for Internal Medicine, Laboratory for Neuroendokrine Immunology
University Hospital

Prof. Dr. Ralf Wagner
Molecular Microbiolgoy & Gene Therapy Unit 
Institute for Molecular Microbiology and Hygiene 

 

 

5. GeneXplain GmbH, Wolfenbüttel

Dr. Alexander Kel

6. AmVac Research GmbH, Martinsried

Dr. Marian Wiegand

 

 

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2011-04-21

Salmonella utilise multiple modes of infection

Scientists from Braunschweig discover new mechanism that helps invading host cells

Wiss_Foto_Salmonella_typhimuriumZellen von Salmonella typhimurium; Foto: Manfred Rohde / HZIScientists from the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany have discovered a new, hitherto unknown mechanism of Salmonella invasion into gut cells: In this entry mode, the bacteria exploit the muscle power of cells to be pulled into the host cell cytoplasm. Thus, the strategies Salmonella use to infect cells are more complex than previously thought. According to the World Health Organization, the number of Salmonella infections is continuously rising, and the severity of infections is increasing. One of the reasons for this may be the sophisticated infection strategies the bacteria have evolved. The striking diversity of invasion strategies may allow Salmonella to infect multiple cell types and different hosts.  

 

Salmonella do not infect their hosts according to textbook model,” says Theresia Stradal, group leader at the Helmholtz Centre in Braunschweig, who has recently accepted a call to the University of Münster. “Only a single infection mechanism has seriously been discussed in the field up till now –without understanding all the details,” adds Klemens Rottner, now Professor at the University of Bonn.  

 

All entry mechanisms employed by Salmonella target the so-called actin cytoskeleton of the host cell. Actin can polymerise into fine and dynamic fibrils, also called filaments, which associate into networks or fibres. These structures stabilise the cell and enable it to move, as they are constantly built up and taken down. One of the most important core elements is the Arp2/3 complex that nucleates the assembly of actin monomers into filaments.  

 

Extensions of the cell membrane are filled with actin filaments. In the commonly accepted infection mechanism, Salmonella abuses the Arp2/3 complex to enter the host cell: the bacteria activate the complex and thus initiate the formation actin filaments and development of prominent membrane extensions, so-called ruffles. These ruffles surround and enclose the bacteria so that they end up in the cell interior. Last year, the research groups headed by Theresia Stradal and Klemens Rottner discovered that Salmonella can also reach the cell interior without initiating membrane ruffles. With this, the researchers disproved a long-standing dogma.  

 

In their recent study, the experts from Braunschweig now describe a completely unknown infection mechanism. The results have just appeared in the latest issue of the leading journal “Cell Host & Microbe”. In this new infection mechanism, Salmonella also manipulate the actin cytoskeleton of the host cell. This time, however, they do not induce the generation of new filaments, but activate the motor protein myosin II. The interplay of actin and myosin II in muscle cells is well known: in a contracting muscle, myosin and actin filaments slide along each other and this way shorten the muscle; it contracts.  

 

In epithelial cells, the contractile structures are less organised but work similarly. Here, actin and myosin II form so-called stress fibres that tightly connect to the membrane. During an infection, stress fibres at the entry site can contract and pull the bacteria into the cell. “This way of infection operates independently from the Arp2/3 complex, the central component of the ‘classic’ infection mechanism,” says Jan Hänisch, who worked on this project as postdoctoral researcher.  

 

Publication: Activation of a RhoA/Myosin II-Dependent but Arp2/3 Complex-Independent Pathway Facilitates Salmonella Invasion. Hänisch J, Kölm R, Wozniczka M, Bumann D, Rottner K, Stradal TE. Cell Host Microbe. 2011 Apr 21;9(4):273-85.

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2011-05-31

German and Indian researchers unite to fight diseases

Joint health research: alliance wants to speed up the transfer of research findings to a medical application.

Deutsch-Indische KonsultationenTo enable research findings to be used for the treatment of patients more quickly: this is the main aim of an agreement which German and Indian scientists have now concluded in New Delhi. The Helmholtz Association and the Indian Council of Medical Research (ICMR) want to set up joint projects which combine basic and clinical research and thus advance the fight against infections and other diseases. The Federal Chancellor Angela Merkel, Professor Annette Schavan, Federal Minister for Education and Research, and the Indian Prime Minister, Manmohan Singh, were present when representatives of both research organisations today signed the cooperation agreement. The meeting formed part of the German-Indian government consultations.

 

By putting their signatures to the document Professor Dirk Heinz, Scientific Director of the Helmholtz Centre for Infection Research (HZI), and Professor Vishwa Mohan Katoch, Secretary of the Indian Ministry of Health, extended a collaboration whose foundation had been laid several years earlier with numerous joint projects.

 

Further research projects, exchange programmes and workshops will now enable a more intense and sustainable transfer of knowledge. “The joint research will concentrate on the development of new anti-infectives, vaccines and diagnostic methods,” explains Professor Heinz. The scientists want to undertake detailed investigations into streptococci infections and hepatitis C, among other things. The joint research will also focus on cancer and other serious illnesses in addition to its work on infections.

 

The partners have particularly high expectations of the expansion of the translational research: the translation, i.e. the rapid transfer of findings from basic research into hospitals, allows new discoveries to reach the application stage much faster. “In both Germany and India there is a great deal of interest in translational research,” says Professor Gursharan Singh Chhatwal from the HZI, who has co-organised many German-Indian cooperation projects in infection research. “The memorandum is intended to strengthen our joint translation endeavours.”
History

The foundation stone for joint German-Indian research was laid back in 1974 with a science and technology agreement between the two countries. In 2006, the HZI teamed up with the Medical University of Hanover (MHH) and the ICMR to found a virtual Centre for Infection Research. The cooperation agreement has been regularly expanded ever since.

 

The successes of the German-Indian research can be seen with streptococci infections, for example. These bacteria attack the skin, cause scarlet fever and tonsillitis. Every year, 900 million people worldwide are infected with the pathogens. 150 different streptococci strains are known - three percent of them can cause rheumatic fever, a serious heart disease in children.

 

In India, six million children suffer from this disease. The large numbers make comprehensive and controlled medical treatment impossible “The dangerous strains were previously unknown. We can now identify them and are just developing a test for them,” says Professor Gursharan Singh Chhatwal from the HZI. “This test narrows down the number of those concerned significantly. It is therefore possible to treat and monitor all of them with penicillin.”

 

The parties to the agreement will set out further details and the funding of the planned German-Indian projects this year, and the implementation will begin next year.

 


The Helmholtz Centre for Infection Research:
 Scientists at the Helmholtz Centre for Infection Research investigate the mechanisms of infections and how they can be fought. Why do bacteria and viruses become pathogens: understanding this will provide the key for the development of new medicines and vaccines. The Helmholtz Centre for Infection Research (HZI) in Braunschweig is a research institution in the Helmholtz Association of German Research Centres funded jointly by the Federal Republic of Germany and the Federal State of Lower Saxony. The Centre’s task is to undertake biomedical research in the field of infection biology and its clinical application and implementation in practice.

 


The Indian Council of Medical Research:
The Indian Council of Medical Research (ICMR) manages all the medical research in India. It is responsible for 27 institutes for health research with some 15,000 scientists overall. Apart from supervising the health systems the ICMR also awards research funds.

 


The Helmholtz Association:
The Helmholtz Association makes its contribution to solving major and urgent challenges faced by society, science and industry by undertaking top-flight scientific research in six research areas: energy, earth and environment, health, key technologies, structure of matter, aeronautics, space and transport. The Helmholtz Association is the largest science organisation in Germany with over 31,000 staff in 17 research centres and an annual budget of around EUR 3.3 billion. Its work follows the tradition of the great natural scientist Hermann von Helmholtz (1821-1894).

 

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2011-06-01

Friendly Fire within the Lungs

HZI researchers show how immune cells mistakenly attack the lungs in chronic obstructive pulmonary disease patients

AlveolusCigarette smoke or a high level of exposure to dust damages our lungs – cells of the immune system are activated within the sensitive respiratory tract and by mistake can attack the healthy pulmonary tissue. This so-called auto-immune reaction can lead to serious chronic inflammations. In a current study researchers at the Helmholtz-Centre for Infection Research (HZI) in Braunschweig succeeded in describing more exactly the role of those particular immune cells that are involved in the development of chronic obstructive pulmonary disease. The results are now being published by the researchers in the current edition of The Journal of Immunology.

 

“Smoking or harmful exposure to dust makes up the initial steps that lead to formation of an inflammatory environment in the alveoli,” says Dr. Dunja Bruder,  head of the research group “Immune Regulation” at HZI. “If the lung is continuously exposed to harmful substances, an inflammatory process that is typical for auto-immune diseases is subsequently set in motion,” adds the scientist. “Cells from the immune system become activated, multiply and then mistakenly attack the body.“ Smoking is recognized as a primary trigger for chronic obstructive pulmonary disease (COPD) – in short, ‘smokers’ cough’. However, COPD is also found in workers that were exposed to high level of dust or fume. Furthermore, in Third World countries women are mainly affected: Here, a continuous exposure to dust from smouldering hearths in closed rooms is a common cause.  In recent years increasing scientific findings indicate that the disease can be considered as an auto-immune disease.

 

Dunja Bruder’s research team has been evaluating for a number of years how the cells of the Pulmonary alveoli communicate with the cells of the immune system. In the current study, the immunologists were able to more specifically describe the role of immune cells that trigger COPD. This involves so-called killer T cells, which naturally destroy virus infected cells. In this manner the immune system is usually quite successful in combating infections. In the COPD case however the persistent provocation of the immune system in the lung leads to a false reaction – the killer T cells attack the body’s own lung cells. 

 

In order to better understand the behaviour of killer T cells and to be able to intervene against the errant immune system, the researchers Dr. Milena Tosiek and Dr. Marcus Gereke from Dr. Dunja Bruder’s team simulated the events in a completely novel mouse model. “The mice carry a protein of the influenza virus on the surface of their alveoli. They also have killer T cells that are able to recognize precisely this viral protein and therefore attack the lung cells. As a result, the mice develop a chronic lung inflammation that is triggered by the killer T cells,” the researcher Dr. Marcus Gereke reports. The researchers isolated the disease-causing cells from the inflamed lung in order to analyse them in more detail.

 

The results surprised the researchers – many immune cells in the inflamed tissue are not at all involved in destruction of the lung cells. Most killer T cells simply “ignored” the lung cells. Only a few cells reacted – but all the more fiercely and with fatal consequences.

 

“This shows how important the healthy balance of the immune cells is,” says Dr. Dunja Bruder. “Even a small quantity of erroneously activated killer T cells could lead to considerable tissue destruction.” 

 

The scientists from Braunschweig are currently carrying out intensive research on the control mechanisms that could circumvent complete destruction of the pulmonary alveoli. “We hope that the understanding of those mechanisms will then lead to a further improvement of COPD treatment in the future,” says Dr. Dunja Bruder.

Publication:
CD+4CD25+Foxp3+ Regulatory T Cells Are Dispenbsable for Controlling CD8+ T Cell-mediated Lung Inflammation. Tosiek MJ, Gruber AD, Bader SR, Mauel S, Hymann H-G, Prettin S, Tschernig T, Buer J, Gereke M, Bruder D. The Journal of Immunology, 2011, Jun 1. 186(11):6106-18.

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2011-07-01

Virtual Institute investigates Virus Infections

Transnational research group examines how viruses evade the immune system

Zellen, die mit einem grünleuchtenden CMV infiziert sind.Cells infected with CMV carrying Green Fluorescent ProteinUnderstanding the tricks and survival strategies of viruses to effectively combat them: That is the goal of the virtual institute VISTRIE that received its funding commitment today. VISTRIE, which stands for “Viral Strategies of Immune Evasion”, is a joint program grant with independent management structures receiving funding by the Helmholtz Association of German Research Centres. Coordinated by the German Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig, five university and non-university research institutions combine their expertise: the HZI, the Medical School Hannover, the TWINCORE Centre for Experimental and Clinical Infection Research in Hannover, the Heinrich-Heine-University in Düsseldorf in Germany and the University of Rijeka in Croatia. Their object of study: the widespread Cytomegalovirus (CMV).

 

“Viruses are the smallest known life form,” says Luka Cicin-Sain, PhD MD, head of the Virtual Institute VISTRIE and head of a young investigator group at the HZI, “if you consider them to be a life form at all.”  For example, viruses cannot propagate. For this, they have to infect a host cell and channel in their genetic information. The host cell is then forced to produce the individual segments of the virus. In the end those building blocks assemble to form new viruses.

 

The immune system is capable to detect and destroy virus infected cells and thus stop the propagation of viruses. However, in the course of evolution, viruses have developed numerous mechanisms to outwit the immune system. For example, they disrupt the communication between immune cells or prevent the killing of the own host cell. “The evolution of viruses is much faster than ours. They are very well adapted to block our immune system,” says Cicin-Sain. “Therefore, viral genes are ideal tools to understand the immune system and the virus defence.”

 

Using CMV as the paradigmatic model pathogen, the VISTRIE researchers will study immune mechanisms and identify critical antiviral processes. CMV belongs to the family of herpes viruses and is globally widespread: Every second German is infected; in some parts of the world up to 99 per cent of the population carry CMV.  Most people do not even notice that they are infected because the virus rests within the host cells and the immune system keeps it in check. Nevertheless, CMV is anything but harmless: Especially for unborn children an infection with CMV can be a threat. “In the US every 1,000th child is being born with disabilities directly caused by a CMV infection,” says Cicin-Sain.

 

The scientists at the new Virtual Institute want to understand how CMV manages to outwit the immune system and evade an immune response. With this knowledge new drugs to treat CMV and other virus infections may be developed in the future. “We also expect to gain new insights into how the immune system reacts upon a virus infection,” says Cicin-Sain. “

 

“With this collaboration at the Virtual Institute VISTRIE we bundle the knowledge of excellent, renowned national and international virologists and shorten the way from bench to patient.” 

 

Virtual Institutes of the Helmholtz Assocation of German Research Centres (HGF)

Virtual Institutes combine the work of Helmholtz centres with universities and international partners. They possess their own managerial structure and are seen as one research centre with partners that are spatially divided. The HGF is funding Virtual Institutes up to five years with a maximum of 600,000 Euros per year from the “Joint Initiative for Innovation and Research” (Impuls- und Vernetzungsfonds). They can be used as preparation for bigger compounds such as Helmholtz Alliances or EU consortia.

VISTRIE („Viral Strategies for Immune Evasion“) will receive a funding sum of approximately 4.5M Euros that will be provided by HGF and participating institutions. The Virtual Institute will start its work in October 2011

 

The  Partners:

Helmholtz Centre for Infection Research, Braunschweig, Germany

Dr. Dr. Luka Cicin-Sain, Junior Research Group “Immune aging and Chronic Infection”

Dr. Melanie Brinkmann, Junior Research Group “Viral Immune Modulation”


Medical School Hannover
, Germany; Virology Department

Professor Martin Messerle, Research Group “Cytomegalovirus”


TWINCORE Centre for Expertmental and Clinical Infection Research
, Hannover, Germany

Professor Ulrich Kalinke, “Experimental Infection Research”


Heinrich-Heine-University
, Düsseldorf, Germany

Professor Hartmut Hengel, University Hospital Düsseldorf, Institute for Virology

Dr. Anne Halenius, University Hospital Düsseldorf, Institute for Virology


University of Rijeka
, Croatia

Professor Stipan Jonjic, Medical Faculty, Department for Histology and Embryology

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2011-07-01

Innovative Vaccines with Nanotechnology

European Research Consortium wants to develop novel vaccination against Hepatitis C.

bmbf logoHCVAX is a European joint project that reaches out to develop a vaccine against hepatitis C based on nanotechnology. The German Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig and its department “Vaccinology and Applied Microbiology” is now a part of the transnational consortium with researchers from Germany, France and Switzerland.

 

More than 170 million people are infected with the hepatitis C virus (HCV) worldwide. Also in Europe this form of hepatitis is a big problem with three per cent of the population affected. The virus is transmitted in operations such as transplantations or by the re-use of syringes for drug usage. Anti-viral treatments are very expensive, have serious side effects and are only effective for some patients. Most of the patients carry the infection for the rest of their lives, with the threat of later developing liver cirrhosis and cancer. Certainly, the most effective way to combat hepatitis C would be a vaccine against the virus – but to date no efficacious vaccine exists.

 

“We will pursue a completely new approach to develop a HCV vaccine,” says Prof. Carlos A. Guzmán, head of the Vaccinology Department at the HZI. With the help of innovative, biocompatible nanogels part of the genetic information of the virus is brought into the body by so-called “RNA replicons”. The synthetic nanogels have a diameter of only a few nanometres and are composed of a biopolymer matrix. Immune cells will take up the nanogels with the genetic information and will produce harmless components of HCV. The immune cell then responds to those foreign structures and will generate memory cells: with this, the vaccination would be successful and from then on one would be protected against an infection with pathogen HCV.

 

By using novel drug amplifiers, so-called adjuvants, the immune response shall be more efficient and targeted. “The HZI has a long-standing expertise in this field. We will incorporate this knowledge into the project to develop more effective vaccines,” says Guzmán. “We want to identify those adjuvants that are most eligible for a use in the nanogel composition. The targeted transport to certain defence cells shall guarantee an optimal immune response.”

 

To exclude side effects, potential vaccine candidates have to be tested in several systems. Promising structures will then be selected for further clinical development.

 

The consortium consists of two companies, three academic institutions and one clinic. They combine their expertise on the field of nanotechnology, biochemistry, immunology, vaccine development and clinical research. “Beyond that we expect that these novel vaccination strategies can be expanded onto the clinical management of other diseases,” says Guzmán.  

 

Funding is granted for the next three years from the “EuroNanoMed Joint Transnational Initiative” of the European Union. The German Ministry for Research and Education is funding the project in Germany.

The Partners:

Federal Department of Economic Affairs (Eidgenössisches Volkswirtschaftsdepartement), Mittelhäusern, Switzerland (coordinator)

Medipol SA, Lausanne, Switzerland


Institut Pasteur, Paris, France


Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung GmbH), Braunschweig, Germany


EDIGmbH, Reutlingen, Germany

Hôpital Cochin, Paris, France

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2011-08-01

Epidemiologist Gérard Krause to head new department at HZI

Using statistics-data to combat pathogens: Long-term studies targeted to improve protection from infections

Gerard KrauseHow infectious diseases spread throughout the population and how one can take countermeasures against this dissemination: these issues are a source of concern for Prof. Gérard Krause, one of the leading epidemiologists in Germany. Krause, who is employed as an expert at the Robert-Koch-Institute (RKI) in Berlin, will also supervise new scientific projects from now on in Braunschweig und Hanover. His goal:  to get to the bottom of the dissemination and progression issues concerning infectious diseases by means of cohort studies. For this purpose, the Helmholtz Centre for Infection Research (HZI) in Braunschweig has appointed Krause to be head of a recently-established department. At the same time, he will also work as professor for infection epidemiology at the Hanover Medical School (MHH). Krause will continue his activities as Department Head at RKI

 

Krause will work on fundamental issues concerning epidemic progression and the respective impact on the population. His department “Epidemiology” seeks to build, with their findings, a solid basis for concrete recommendations regarding vaccinations, concepts for hygiene within the hospital, measures for food safety, as well as protection against infection in public health service.

 

For example, as Chief Infection Epidemiologist at the Robert-Koch Institute (RKI), Krause investigated the origins of the EHEC outbreak in the early summer of 2011 and was able to identify consumption of bean sprouts as the source of the infection. “Our work consists primarily of evaluations of standardised questionnaires, clinical examinations and laboratory proofs, with the aid of statistical procedures”, explains Krause. “Ideally, one can retrace pathogens back to the source of their outbreak, characterise dissemination patterns, recognise risk factors and measure the effectiveness of preventive measures”.

 

The pathogens we examine are diverse and range from viruses like influenza, which involve the respiratory passages, to bacteria such as MRSA (Methicillin-resistant Staphylococcus aureus), which are resistant against many antibiotics. 

 

The HZI has at their disposal a broad spectrum of expert human resources to conduct research on both the underlying mechanisms of these diseases at the level of the pathogens, and on the organisms affected by these pathogens. New research projects with an epidemiological approach are thus formed to reveal, for example, the dissemination characteristics of pathogens and the risk factors for certain population groups. In combination with pre-existing HZI scientific insights regarding pathogens and their infection mechanisms, the scientists provide new epidemiological methods and models from studies. “Here at HZI, I can, in collaboration with my colleagues, conduct a systematic search for answers to questions that we encounter again and again in our practical tasks at the RKI”, says Krause. “The molecular- epidemiological laboratory in the new department will assure a smooth transition between our different research methods.”

 

A primary focus for the new department “Epidemiology” will be a large-scale cohort study of the Helmholtz Association and other research facilities, in which 200,000 individuals throughout Germany will be examined on a regular basis over several decades. With the help of new findings, evaluations will be made regarding which factors increase infection risks, what kind of delayed reactions certain infections have and how these can be avoided. 

 

“I am pleased to see that we have been able to complement, so appropriately, the expertise of the HZI with the efforts of such an outstanding scientist as Gérard Krause”, says Prof. Dirk Heinz, Acting Scientific Executive Director of the HZI. And Prof. Reinhard Burger, President of the Robert-Koch-Institute adds: “We are expecting many new insights from this special form of cooperation. Basic research at HZI and the practice-based epidemiology at the RKI are able to mutually inspire one another, thus generating new approaches.”

 

Gérard Krause studied Medicine at the University of Mainz and received in 1993 his Doctor of Medicine diploma in tropical hygiene. From 1993 to 1998 he worked as medical practitioner and scientific co-worker in the areas of Tropical Medicine, Internal Medicine and Hospital Hygiene at the University Clinic Heidelberg, a hospital in Osnabrück and the University of Freiberg. He had various research and training experiences in England, Ecuador, Columbia, Burkina Faso and Nigeria and was employed as Epidemic Intelligence Service Officer in the Centers for Disease Control and Prevention in Atlanta, USA. In 2000 he came to the RKI in Berlin, where he supervised the subject area Surveillance and has been Head of the Department Infection Epidemiology since 2005. In the same year, he was promoted to Professor in the subject area Epidemiology and Hygiene at the Charité in Berlin. In 2008 he founded the Master’s study programme for Applied Epidemiology at the Charité. Gérard Krause is a specialist medical practitioner in tropical medicine and emergency medicine.

 

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2011-08-15

Hide and Seek in the Tumour

Researchers examine how bacteria form biofilms in cancerous tissue to hide from the immune system.

 Salmonellen TumorSalmonella bacteria cause several diseases – however, they have features that make them very interesting for cancer medicine: The germs migrate into tumours and lead to the death of aberrant cells. Scientists from the Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung) in Braunschweig, Germany, now discovered that Salmonella form communities within the tumour. They develop so-called biofilms as a reaction upon the attacks of the immune system. On the one hand, a biofilm protects the bacteria. On the other hand, it improves the therapeutic effect – a very useful side effect. The results have now been published in the latest issue of the scientific journal “Cellular Microbiology”.

 

For years, the HZI research group “Molecular Immunology” is investigating how Salmonella help to defeat tumours in mice. They already found out: Immune cells that recognize the bacteria send out a certain messenger substance. This makes the blood vessel within the cancerous tissue accessible for bacteria to enter the tumour. Since the blood vessels in the tumour are more permeable, blood accumulates within the cancerous tissue and a necrosis develops – the aberrant cells die off.

 

When the scientists took a deeper look onto how the bacteria are able to survive within the cancerous tissue and assist in destroying the tumour, they observed something that was previously unknown:  The bacteria form a biofilm within the tumour.

 

A biofilm is a community of bacteria that live together within a protective slime layer. Biofilms can be found everywhere on almost all surfaces, some of them helping our body such as the bacterial communities in our gut or on our skin. They protect against infections. However, other biofilms are a threat for the body such as cavity causing bacterial communities on our teeth. Even more severe are the problems caused by biofilms within the lungs of patients suffering from cystic fibrosis. “Here, the bacteria can multiply in the tenacious mucus and are very well protected against antibiotics or the immune system,” says Dr. Siegfried Weiss, head of the HZI research group “Molecular Immunology”. Until now only few possibilities exist to study such unhealthy biofilms which is necessary to develop new therapies or drugs to fight them.

 

Dr. Katja Crull, scientist in Dr. Weiss’ research group examined how biofilm formation and tumour-fighting are connected. For this, she infected tumour-bearing mice with genetically modified Salmonella that are unable to form biofilms. Interestingly, without the bacterial community the colonization of the tumour and its destroying was severely deteriorated.

 

As biofilms help to protect against the immune system, the scientists then infected tumour-bearing mice that lack certain immune cells with normal, unmodified Salmonella. Also under these conditions the bacteria did not form biofilms within the tumour. “Thus, the Salmonella hide within the tumour from certain immune cells and are protected in their biofilm against the immune system,” says Dr. Katja Crull. What actually increases the danger of the bacteria leads to an improved fight against cancerous tissue. To purposefully use these features may one day enable innovative cancer therapies.

 

Dr. Siegfried Weiss emphasizes that tumours could furthermore now be a completely new model to investigate biofilm formation within tissues. “Such experiments are still a big challenge and only few models exist until now. Studies on biofilms in tumours may be a new approach to develop and test new drugs and therapies.”

 



Publication:

Biofilm formation by Salmonella enterica serovar Typhimurium colonizing solid tumours. Crull K, Rohde M, Westphal K, Loessner H, Wolf K, Felipe-López A, Hensel M, Weiss S. Cell Microbiol. 2011 Aug; 13(8). doi: 10.1111/j.1462-5822.2011.01612.x.

 

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2011-08-17

Molecular Tricks of the Motile Malaria Pathogen

How Plasmodium falciparum is able to quickly alter its cytoskeleton

ADF ProteinIt infects men and mosquitoes, changes its form multiple times, and moves very elegantly and rapidly through the body of its host: Plasmodium falciparum, the causative agent of malaria, shows an astonishing versatility and motility. Researchers from the Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) have now investigated the molecular basis behind this behaviour. They discovered that the pathogen is able to regulate its cytoskeleton very flexibly in an unusual way – with biochemical tools that, to this extent, are not known in unicellular organisms. The results have now been published in the current issue of the scientific magazine "Journal of Biological Chemistry". The work was done in a German-Finnish-Swedish collaboration at the Centre for Structural Systems Biology (CSSB) at the German Electron Synchrotron (DESY) in Hamburg.

 

The cytoskeleton is a molecular scaffolding structure in highly developed cells. In the malaria parasite, it plays a pivotal role during motility within the infected host and during infection of liver or red blood cells. The HZI researchers have now deciphered how certain factors regulate and affect the cytoskeleton of the malaria pathogen – utilizing proteins that no other Protozoa possess.

 

More than 300 million people worldwide are infected with the malaria pathogen Plasmodium falciparum, causing one million fatalities every year – half of them children. 90 percent of the patients live on the African continent. At the moment, no protective vaccine against malaria is available. Chloroquine- or artemisinin-based drugs help; resistance against the existing drugs is increasing, however.

 

Plasmodium falciparum displays a very sophisticated and complex life cycle that includes different developmental stages within mosquitoes and human beings. The pathogen enters our body by a sting from an infected Anopheles mosquito. Soon after, the parasites infest liver cells, where they multiply to subsequently get back into the blood stream. The next targets are the red blood cells, in which they mature – leading to rupture of the red blood cells and severe anaemia. Furthermore, the pathogens produce toxins that affect the host cells and cause the well-known fever attacks.

 

To move in a targeted manner within its host, P. falciparum is dependent on a fine-tuned regulation of its cytoskeleton, which is composed of actin building blocks. Actin can further congregate to fibres, so-called microfilaments, and regulatory proteins adjust the length of these filaments. Dr. Inari Kursula, a scientist at the HZI Structural Biology Division, took a deeper look at two of the regulatory proteins, the actin depolymerizing factors ADF1 and ADF2, which control the assembly and dismantling of the actin filaments. Both factors show very different behaviour, despite being closely related to each other. While ADF1 only binds the single actin components of the cytoskeleton and prepares them for the integration into the microfilament, ADF2 is doing the exact opposite: It breaks up actin filaments.

 

"It is very unusual that Plasmodium possesses two ADF proteins," says Dr. Inari Kursula. These parasites belong to the family of unicellular Protozoa, which usually only have a single ADF. Additionally, according to Dr. Inari Kursula, the actin filaments of these parasites are very short compared to actin filaments of its host.

 

To investigate the structural and functional differences of both Plasmodium ADFs, Dr. Inari Kursula deciphered the structure of both proteins with her colleagues at the German Electron Synchrotron (Deutsches Elektronensynchrotron, DESY) and University of Oulu, Finland, using highly sophisticated synchrotron radiation at both DESY and MAX-Lab, Lund, Sweden. The team discovered that the filament-severing ADF2 protein possesses a kind of molecular shovel that slots itself between the building blocks of the filament, resulting in the cleavage of the filament. ADF1 lacks the structures required for filament binding and rather functions as an efficient monomer sequesterer, providing a constant pool of new building blocks to be rapidly inserted into the growing filament.

 

This unusual regulation of the cytoskeleton may be an adaptation of the malaria pathogen to its two very different hosts, man and mosquito, says Dr. Inari Kursula. As pathogens, Plasmodia have to quickly alter and rearrange their cytoskeleton, in order to be motile and to infect cells. Both the short microfilaments and the two different ADFs play an important role during those processes.

 

"New knowledge about these unique mechanisms in the malaria pathogen may help to develop alternative drugs or new therapies," concludes Dr. Inari Kursula.  

Publication: Crystal structures explain functional differences in the two actin depolymerization factors of the malaria parasite. Singh BK, Sattler JM, Chatterjee M, Huttu J, Schüler H, Kursula I. J Biol Chem. 2011 Aug 12;286(32):28256-64.

Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI):

The Helmholtz Centre for Infection Research contributes to the achievement of the goals of the Helmholtz Association of German Research Centres and to the successful implementation of the research strategy of the German Federal Government. The HZI focuses on the programme "Infection and Immunity". The goal of the programme is to solve the challenges in infection research and make a contribution to public health with new strategies for the prevention and therapy of infectious diseases.

Deutsches Elektronen-Synchrotron (DESY):

DESY is one of the world's leading accelerator centres and a member of the Helmholtz Association. DESY develops, builds and operates large particle accelerators used to investigate the structure of matter. DESY offers a broad research spectrum of international standing focusing on three main areas: accelerator development, construction and operation; photon science; particle and astroparticle physics.

Centre for Structural Systems Biology (CSSB):

Located at the DESY campus in Hamburg, the inter-disciplinary Centre for Structural Systems Biology (CSSB) unites partners from various universities and research facilities from Lower-Saxony, Hamburg and Schleswig-Holstein under scientific co-ordination of the Helmholtz Centre for Infection Research (HZI). The CSSB is creating a bridge between structural biology and systems biology; this is the place where biologists, chemists, physicians, physicists and engineers are jointly evaluating the interactions between pathogens and their hosts. In this regard, DESY is able to make available to them, unique in Germany, the following: PETRA III, the world’s most brilliant storage-ring-based X-ray source, and FLASH, the world’s first-ever X-ray free-electron laser in the vacuum ultraviolet and in the soft X-ray region. On this basis, researchers can examine biological samples in various styles – from the structural analysis of individual molecules to real-time representation of the functions within living cells.

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2011-08-22

Dirk Heinz new Scientific Director of HZI

Successor of Jürgen Wehland now officially confirmed.

Portrait des Wissenschaftlichen Geschäftsführers des Helmholtz-Zentrums für Infektionsforschung Prof. Dr. Dirk HeinzScientific director of the Helmholtz Centre for Infection Research Prof. Dr. Dirk HeinzThe Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig, Germany, has a new Scientific Director. The German Ministry for Education and Research (BMBF) has appointed the structural biologist Prof. Dirk Heinz with effect from August 1 as successor of Prof. Jürgen Wehland who passed away a year ago. Heinz has been acting Scientific Director since September 2010. His future plans include the expansion of cooperations with academic partners and industry to establish a better link between basic research and clinical application.

 

Dirk Heinz studied chemistry and biochemistry in Freiburg before specializing in structural biology during his PhD at the University of Basel. After a research stay in the US he returned to Freiburg. In 1998 he changed to the German Research Centre for Biotechnology, which is now the HZI. Since 2003 he was head of the department and division of structural biology at the HZI. Dirk Heinz is member of numerous scientific organisations, including the Academy of Sciences in Hamburg and the European Molecular Biology Organisation (EMBO). Furthermore he holds positions in several scientific professional societies.

 

Heinz sees the great challenges of the future in "translation" – the effective bridging between scientific findings and clinical medicine – as well as in the expansion of interdisciplinary and transregional alliances in infection research. This includes the German Centre for Infection Research (DZIF), a network of outstanding research institutions initiated by the BMBF. The DZIF has been established to bundle scientific expertise in infections and to promote the implementation of concepts for the development of new therapies. "The HZI as one of selected institutions will play an important role within the DZIF," says Heinz. "We want to fulfil this mission and thus contribute to the solution of urgent medical problems."

 

One of Prof. Heinz' high priority goals is the establishment of a combined centre for Drug Research and Functional Genomics on the HZI campus. There, natural compounds shall be investigated and examined that may help in fighting infections. Another focus will be the role of the genes during infections, with a focus on human genes as well as the genes of the numerous pathogens.

 

"Dirk Heinz is renowned as an analytically thinking scientist and a dedicated, energetic leader," says Ulf Richter, Administrative Director of the HZI. "I am convinced that he will lead the Centre successfully focusing on infection research and I am looking forward to working with him."

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2011-08-25

The Lung in a Cell-Culture Model

New research project aims to help in replacing animal experiments

Labor_Dagmar_WirthLaborimpressionen Arbeitsgruppe Dagmar Wirth, Modellsysteme für Infektion und Immunität Untersuchungen an transgenen MäusenFollowing infections of lung cells through various pathogens in the culture dish: this is the goal of a new joint project of two Helmholtz research groups. The scientists are attempting to reconstruct lung cells from mice in a stable in vitro model, in order to conduct research on the intrusion of pathogens such as viruses and bacteria and to test new active pharmaceutical ingredients. The project, in which scientists from the Helmholtz Centre for Infection Research (HZI) and their Saarbrücken branch office, the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), are participating, has the potential to replace numerous animal experiments in the future.

 

The “Centre for the Documentation and Evaluation of Alternatives to Animal Experiments (ZEBET)” at the Federal Institute for Risk Assessment (BfR) is now funding the project “Conditional Immortalization of Alveolar Epithelia Cells (CILIA)” for the duration of three years.

 

“It is our plan to immortalize cells from the deep lung of mice and to establish them as a model”, says Dr. Nicole Daum from HIPS. “With these alveolar epithelia cells, we can then for example examine how influenza viruses cross the pulmonary barrier.” In the department “Drug Delivery”, the scientists under the leadership of Professor Claus-Michael Lehr are conducting research that involves the characteristics of biological barriers such as lung, intestinal tract and skin. “We could also test new active ingredients on permanent lung cells, since the model represents a facsimile of the mouse lung, enabling in part a replacement of experiments on animals”, Daum explains. So that a drug can reach its place of action, it must be able to cross the tissue barrier.

 

Immortalizing cells and stimulating them to multiply is a procedure established for other cell types. First of all, the researchers infect the cells with viruses into which they have inserted certain genes. The viruses then do the rest of the work: They introduce the genes in a stable manner into the genetic material of the cells – the activity of these genes motivates the cell to split and multiply. Up until now however, this procedure with epithelial cells of the pulmonary alveoli, always led to the loss of barrier characteristics. Examinations on living animals have therefore always been unavoidable. The working group of Dr. Dagmar Wirth at HZI has nevertheless developed a procedure with which cells, despite the immortality, continue to retain their characteristic features.

 

“With another cell type, we have succeeded in stimulating controlled growth, without having to change the characteristics of the cell”, says Dagmar Wirth. The special thing about this model is: In addition to the gene for on-going proliferation, there is also a molecular on- and off-switch. “We stimulate cell division only when we need to. Now we would also like to install such a switch into the lung epithelial cells using an appropriate gene for division, enabling the cells to retain their characteristics of a biological barrier over the long term.” The cells must however be able to, despite the newly introduced genes, form a tight and if possible impermeable layer. If this is successful, it will be possible to implement them for various examinations instead of living mice. Over the long term, it would be a further step towards the “artificial lung” in the cell culture.
 
Helmholtz Centre for Infection Research:


The Helmholtz Centre for Infection Research contributes to the achievement of the goals of the Helmholtz Association of German Research Centres and to the successful implementation of the research strategy of the German Federal Government. The HZI focuses on the programme "Infection and Immunity". The goal of the programme is to solve the challenges in infection research and make a contribution to public health with new strategies for the prevention and therapy of infectious diseases.
 
Helmholtz Institute for Pharmaceutical Research Saarland:


The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) is a branch office of the Helmholtz Centre for Infection Research (HZI) in Braunschweig and was founded together with the Saarland University in 2009. Where do new sustainable active ingredients against widespread infections come from, how can they be optimized for the application to humans and how are they delivered efficiently to the target site? The scientists at HIPS are searching for answers to these questions by deploying highly modern methods of pharmaceutical sciences.

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2011-09-07

Intimate Binding to Intestinal Cells

Researchers from the HZI investigate the attachment of EHEC bacteria in detail.

 

 Elektronenmikroskopische Aufnahme von EHECEvery year infections with "entero-hemorrhagic Escherichia coli" bacteria (EHEC) keep researchers in industrialised countries busy. During an infection the bacteria colonize the intestinal mucosa and produce a toxin that causes bloody diarrhoea, leading to severe complications. Scientists from the Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig, Germany, have now in cooperation with German and American colleagues uncovered new details of how canonical EHEC, serotype O157:H7, attach to intestinal cells. They deciphered at the atomic level how this binding works: Only three amino acids, building blocks of a certain bacterial molecule, account for the firm connection between bacterium and intestinal cell. The results have now been published in the latest issue of the scientific magazine "Structure".

 

"EHEC are pathogenic relatives of E. coli bacteria that are part of our healthy intestinal flora," says Professor Theresia Stradal who recently changed from the HZI to the University of Münster. EHEC enter our body mainly via contaminated food. Within the body they tightly bind to the surface of intestinal cells. "Doing so, they inject a protein cocktail via a 'molecular syringe' into the host cell, initiating a so-called signal cascade." In the course of these processes, the bacteria firmly anchor on the surface of the intestinal cell, sitting on a small pedestal formed by the host’s cytoskeleton. Production of the diarrhoea causing toxin is independent of these processes.

 

The stable contact between EHEC and intestinal cell is mediated through three proteins – the bacterial factors Tir and EspFU that are being translocated into the host cell, and IRSp53 of the intestinal cell. The latter accumulates beneath the bacterium at the inner cell surface, bridging to host cell proteins that initiate and maintain pedestal formation. This connection was independently discovered and described in 2009 by Theresia Stradal's research group and by her American colleagues for the first time.

 

Structural biologists of the HZI have now deciphered the interaction between the EHEC factor Tir and the human protein IRSp53. They analysed the atomic structure of both proteins during their interaction and discovered that two Tir proteins and a single two-chain IRSp53 bind in a key-lock fashion. Notably, just three amino acids of the bacterial protein Tir are essential to mediate this firm interaction, fitting in a newly discovered binding groove on the surface of the host protein IRSp53. "The stability and specificity was very surprising to us," explains Dr. Konrad Büssow, head of the HZI research group "Structural characterization of pathogen defence factors".

 

The change of just one single amino acid on either the bacterial Tir or human IRSp53 already weakened or even abrogated binding of the two proteins. "This work unveils for the first time atomic details of this interaction between EHEC Tir and host IRSp53," says Büssow.

 

"With our knowledge about this interaction we may also gain new insight into the cellular roles of IRSp53 in the future," says the PhD student Jens de Groot who did a major part of the experimental work together with Kai Schlüter, also PhD student, "since bacteria tend to usurp already existing binding sites for their purposes, and this one was as yet unrecognized."

 

 

Publication: de Groot JC; Schlüter K; Carius Y; Quedenau C; Vingadassalom D; Faix J; Weiss SM; Reichelt J; Standfuß-Gabisch C; Lesser CF; Leong JM; Heinz DW; Büssow K; Stradal TEB. Structural Basis for Complex Formation Between Human IRSp53 and the Translocated Intimin Receptor Tir of Enterohemorrhagic E. coli. Structure, 2011 Sep 7;19(9):1294-1306.

 

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2011-09-13

The Exhausted Immune Defence

Scientists from HZI unravel why immune cells tolerate bacteria during a chronic infection.

Teaser Staph aureusAfter an initial acute infection, Staphylococci can persist in our body for a long period of time leading to chronic disease. Scientists from the Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig, Germany, have revealed why the body's defense mechanisms fail to completely eliminate the bacteria during a chronic infection. The continuous confrontation with the pathogen makes a certain type of immune cell, the so-called T cells, from working properly – these cells become completely exhausted and can no longer recognize and fight the persistent bacterium. These results have been published in the latest issue of the scientific journal "EMBO Molecular Medicine".

 

Immunologists call this state of T cells fatigue "anergy" which means a lack of reaction to the infecting microbe. Generally, anergy is a protective mechanism for silencing autoreactive immune cells and prevents the immune defence from erroneously attacking our own body tissue, says Dr. Eva Medina, head of the HZI research group "Infection Immunology". Although it has been shown before that T cells can become anergic during chronic viral infections, it is a rather unusual event in the context of bacterial infections.

 

Staphylococci like the well-known strain Staphylococcus aureus are normal components of the bacterial flora harmlessly colonize our skin and body cavities such as the nose. This changes when S. aureus finds a way to invade and spread throughout our body, for example via a wound or skin cut, giving rise to severe complications including infections of the lungs, heart, bones and joints and other vital organs. In certain situations, these infections are refractory to antibiotic treatment producing chronic and recurrent infections.

 

Using a mouse model of S. aureus chronic infection that mimics the infection in humans, the researchers were able to show that during the early infection, the so-called acute phase, the immune defence functioned properly: “T cells recognized and combated the pathogen. But later on, the immune response became less and less energetic even though the bacteria are still present," says Christina Ziegler who investigated this theme in her PhD thesis. "The exhaustion of T cells and their incapacity to fight the pathogen marks the point when the infection starts to become chronic”.

 

The scientists have also tried to identify the molecular mechanisms responsible for the disability of the T cells to react during chronic infection. They found that a defect in the transmission of the cellular signals induced from the surface receptor after bacteria recognition impeded the activation response of the T cells. "We believe that during the chronic infection the continuous activation of T cells by the unremitting presence of bacteria provokes a disruption within the cell signalling circuits similar to an electrical short cut".

 

“If we know how to hamper the development of T cell anergy and keep them fully functional during staphylococcal chronic infection we will be able to develop new immunotherapies for the treatment of affected patients”.

 

 



Article
:
Ziegler C, Goldmann O, Hobeika E, Geffers R, Peters G, Medina E. The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen-reactivity to in vivo anergy.
EMBO Mol Med. 2011 Sep 2. doi: 10.1002/emmm.201100173. [Epub ahead of print] 

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2011-11-09

Immune surveillance against cancer

Early stage tumor suppressionthrough immune surveillance: HZI researchers describe a new mechanism

 Mikroskopische Aufnahme von Lebergewebeschnitten, die seneszente Zellen enthalten.Helmholtz-Zentrum für InfektionsforschungLiver tissue section with a senescent liver cell directly in the center of the image. The cell is surrounded by small cells, attacking immune cells that have recognized and will eliminate the senescent cell (Hämatoxylin-Eosin-stained section). Liver cancer (hepatocellular carcinoma) is one of the most common malignancies worldwide. In the majority of cases hepatocellular carcinoma develops after liver damage due to chronic Hepatitis B- or C virus infections. Researchers at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and Hanover Medical School have now revealed how an intact  immune system is able to recognize and eliminate premalignant liver cells at an early stage. Cells which are at a high risk for malignant transformation – e.g.  as a result of chemical stress or radiation – often exit from their normal life cycle and enter a state of arrest, known as “senescence”. Together with co-workers from other research institutions the HZI scientists discovered that such senescent cells make themselves visible for the immune system, e.g. by secreting factors which can attract immune cells. As a result, senescent cells are continuously cleared by the immune system, a mechanism which was designated as “senescence surveillance”. The researchers found that a continuous immune surveillance of senescent hepatocytes is important to suppress the development of liver cancer and they propose that a mechanism, similar to the one shown in liver, may play a key role in tumor suppression in other organs as well. The results of the study have now been published in an advance online release by the renowned scientific journal “Nature”.

 

At the end of their life cycle or if their genetic information gets damaged, cells either undergo a program of controlled cell death or, alternatively, enter a kind of “hibernation”, the so-called cellular senescence program. This arrest prevents defective cells from uncontrolled proliferation and thus avoids the formation of tumors. Professor Lars Zender, head of the HZI research group Chronic Infections and Cancer and his team were able to demonstrate that the immune system plays a crucial role in the continuous surveillance of these resting cells. “By this means it prevented that the damaged cells can acquire further alterations which may result in the development of aggressive tumors”, explains Lars Zender.

 

To analyze how the senescence program and the immune system interact to prevent tumor development Lars Zender and his team used a genetic method to induce the senescence program in liver cells of laboratory mice. “It was impressive to see, how efficient the immune system recognizes and eliminates modified cells”, says Zender. After a few weeks the modified, senescent cells were eliminated.

 

In immunodeficient mice which are missing so called T-helper cells, researchers were able to observe that senescent liver cells were not cleared but rather progressed into liver carcinomas. “This clearly shows how important the surveillance of senescent cells is – a task carried out by the immune system, and specifically coordinated by T-helper cells”, says Zender.

 

This newly identified mechanism may also help to explain why HIV-positive patients have an increased risk of developing liver cancer. To investigate this phenomenon, researchers determined the number of senescent cells in the livers of patients with chronic Hepatitis C virus infection who were also HIV-positive. The results were compared to the numbers of senescent cells in livers of Hepatitis C virus infected patients without concomitant HIV infection. “As expected, in the group of Hepatitis C/HIV co-infected patients the number of senescent cells were strongly increased”, says Zender. “In HIV patients, the activity of T-helper cells is impaired and, as a consequence, - senescent liver cells probably cannot be eliminated effectively.”

 

The authors of the study hope that the newly discovered mechanism will enable new strategies for cancer prevention and therapy.

Publication:

Senescence surveillance of premalignant hepatocytes limits liver cancer development.

Tae-Won Kang, Tetyana Yevsa, Norman Woller, Lisa Hoenicke, Torsten Wuestefeld, Daniel Dauch, Anja Hohmeyer, Marcus Gereke, Ramona Rudalska, Anna Potapova, Markus Iken, Mihael Vucur, Siegfried Weiss, Mathias Heikenwalder, Sadaf Khan, Jesus Gil, Dunja Bruder, Michael Manns, Peter Schirmacher, Frank Tacke, Michael Ott, Tom Luedde, Thomas Longerich, Stefan Kubicka and Lars Zender

Nature, Advanced Online Publication, DOI: 10.1038/nature10599

 

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Senesence Figure 1:

Liver tissue section with a senescent liver cell directly in the center of the image. The cell is surrounded by small cells, attacking immune cells that have recognized and will eliminate the senescent cell (Hämatoxylin-Eosin-stained section).

 

Senesence Figure 2:

 

Liver tissue section with a senescent liver cell directly in the center of the image. The senescent cell is stained homogenously in brown colour. Small immune cells are located in close proximity to the senescent cell and will eliminate the senescent cell.

 

Senesence Figure 3:

 

The figure shows a liver tissue section. Multiple cells have been visualized using a fluorescence dye. A senescent liver cell (orange) is dying as it is being attacked by different immune cells. Among the attacking immune cells are cells of the innate immune system, stained in green (monocytes, macrophages, neutrophilic granulocytes) as well as cells of the adaptive immune system, stained in purple (T- lymphocytes). T-helper lymphocytes “instruct” the green cells to kill the orange stained senescent liver cell.

 

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2011-12-04

Understanding the molecular production line

How natural polyketides are produced “in assembly lines”: HZI researchers decode the molecular structure of synthesizing enzymes

 Das funktionelle CinFDas funktionelle CinF ist aus vier CinF Molekülen aufgebaut, die sich gegenseitig bei der Bindung des Substrates unterstützen.From deadly toxins to curative antibiotics: The polyketides, a class of biologically active compounds, comprise a multitude of metabolites from plants, fungi, bacteria and other organisms.  How does nature produce this remarkably broad spectrum? Researchers of the Helmholtz Centre for Infection Research (HZI), Braunschweig, the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and Saarland University in Saarbrücken have now reached a milestone on the way to understanding these processes. They have decoded the structure and function of an enzyme that provides and prepares an important component for the stepwise assembly of a polyketide molecule. The team of scientists was the first to elucidate how the enzyme recognizes, binds and activates specific precursor components. The results of this study have now been published by the renowned scientific journal “Nature Chemical Biology”. The researchers hope that they soon will be able to “reprogram” the polyketide synthesis in cells – and thus yield new substances with pharmaceutical properties.

Polyketides make up one of the most extensive classes of natural products. Many of them have been discovered and isolated from microorganisms and plants. Their biological activities are remarkably manifold: they serve as signaling molecules, natural pigments and “defense weapons” against antagonists. The antibiotic Erythromycin, the chemotherapeutic agents Doxorubicin and Epothilon and the antiparasitic drug Avermectin are prominent examples. In spite of their diversity, polyketides are produced via a common biosynthetic pathway.

The stepwise linking of single precursor elements that leads to the formation of polyketides in microorganisms is accomplished by special enzyme complexes, the so-called polyketide synthases. “The production of polyketides is basically assembly line work”, explains Professor Rolf Müller, Director of HIPS as well as Professor for Pharmaceutical Biotechnology at Saarland University. “The polyketide synthase is an analogue to a factory’s production line. The enzyme accepts an element from a certain supplier unit and another element from a different one. Comparable to car production, where specific units provide only doors, others only engine hoods and so on. The polyketide synthase chemically links all elements in order to form a complete polyketide.”

Using the reference bacterium Streptomyces, the researchers focused their attention on the suppliers that provide the single elements. The suppliers studied represent a class of proteins assigned the complex name „crotonyl-CoA carboxylase/reductase“, short CCR. They fulfill the task of delivering elements to the synthases; each CCR is specialized to provide only certain elements. “The question now was: How do the CCRs help to accomplish the remarkable variety of polyketide structures?” 

The researchers analyzed the biochemistry and the molecular structure of one particular CCR. They chose the enzyme 2 octenoyl-CoA synthase, short CinF. „We were the first to see at atomic resolution how CinF binds its substrate”, says Dr. Nick Quade, scientist in the Department of Molecular Structural Biology at the HZI. A pocket in the supplier protein enables the binding partner to directly interact with CinF. Finally the researchers compared the CinF binding pocket structure to pocket structures of other CCRs that provide distinct substrates. 

Binding pockets of the latter are exactly complementary to their respective substrate, similar to the lock and key principle. The researchers found that CCRs choose their substrates depending on the pocket size: Some CCRs are specialized in short-chained molecules, others preferentially “fish” for long-chained elements, and then prepare them for the integration into the polyketide.

As polyketides often show interesting medical effects, the scientists hope to gain valuable information for the development of novel pharmaceutics. “We want to understand the way CCRs work and provide single elements”, explains Professor Dirk Heinz, Scientific Director at the HZI and co-author of the publication. “The long-term goal is to specifically regulate the assembly and modification of polyketide components and thus to produce customized medical products.” 

Original publication: 

Unusual Carbon Fixation Giving Rise to Diverse Polyketide Extender Units. Nick Quade, Liujie Huo, Shwan Rachid, Dirk W. Heinz, Rolf Müller.

Nature Chemical Biology,Advanced Online Publication, DOI: 10.1038/NChemBio.734

http://dx.doi.org/dx.10.1038/NChemBio.734

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2012-01-03

Treasure Hunt in the Bacterial Genome

EU funds research on Actinomycetes with 1.5 million Euro

 

A research project aimed at finding new medical compounds in bacteria has now been granted financial support from Brussels. The European Research Council (ERC) will fund the work of Dr. Andriy Luzhetskyy, a junior scientist investigating the genetics of Actinomycetes. This particular group of microorganisms produces a variety of important natural products which play a pivotal role in modern drug-based therapy of various diseases. With their help, Luzhetskyy intends to discover new potential drugs suitable for clinical use, e.g. as antibiotics. Over the next five years, he will receive a so-called “ERC Starting Grant” totalling 1.5 million Euro. Luzhetskyy heads a research group at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), a branch of the Helmholtz Centre for Infection Research (HZI) in Braunschweig. 

Picture of expression of the gusA gene in Streptomyces Tü6071Expression of the gusA gene in Streptomyces Tü6071Actinomycetes produce and release an extraordinary wealth of chemical compounds. Some of these substances kill or inhibit other organisms – they presumably evolved to give the Actinomycetes an advantage in competing for food and habitat. Humans can also benefit from these effects, as antibiotics and antitumor drugs belong to the broad spectrum of Actinomycete metabolites.

 

Scientists have already identified several natural compounds from Actinomycetes, but not nearly all of them. Many “treasures”  are still hidden within the bacterial genome. “Actinomycetes have about 8000 genes”, Luzhetskyy explains, “The function of more than 3000 among them is still unknown.” One of the reasons is that whole complexes of genes “lie dormant” and are not active under normal laboratory conditions. In most cases it is still unknown how they are switched on and which substances they produce in an active state.

 

Luzhetskyy and his team intend to activate such genes in the microbial genome. They will develop genetic engineering methods especially for Actinomycetes and use them to switch on silent genes and effectively initiate metabolic pathways.

 

Luzhetskyy has five years to look for hidden natural compounds. “At the end, we want to establish a new technological platform which allows access to novel natural products”, says Luzhetskyy, “and we hope that new drugs will be developed based on these substances.”

Further information:

 

ERC Starting Grants

The European Research Council (ERC) has been founded by the European Commission in order to encourage high quality research in Europe through competitive funding. ERC Starting Grants aim to support up-and-coming research leaders who are about to establish or consolidate a proper research team and to start independent research in Europe. The scheme targets promising researchers who have proven the potential of becoming independent research leaders. 

 

 

 

The Helmholtz Centre for Infection Research (HZI) 

The Helmholtz Centre for Infection Research contributes to the achievement of the goals of the Helmholtz Association of German Research Centres and to the successful implementation of the research strategy of the German Federal Government. The HZI focuses on the programme "Infection and Immunity". The goal of the programme is to solve the challenges in infection research and make a contribution to public health with new strategies for the prevention and therapy of infectious diseases.

www.helmholtz-hzi.de

 

 

 

The Helmholtz Insititute for Pharmaceutical Research Saarland 

The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) is a branch of the Helmholtz Centre for Infection Research (HZI) in Braunschweig and was founded together with the Saarland University in 2009. Where do new compounds against widespread infections come from, how can they be optimised for the application to humans and how are they delivered efficiently to the target site? The scientists at HIPS are searching for answers to these questions by deploying highly modern methods of pharmaceutical sciences.

www.helmholtz-hzi.de/HIPS

 

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2012-01-13

Cancer Research Award for HZI Scientist

January 16th, 2012: Lars Zender receives Johann-Georg-Zimmermann Award

Prof. Dr. Lars Zender has received one of the most distinguished German cancer research awards. The Johann-Georg-Zimmermann Award, endowed with 10 000 Euro, highlights Zender’s findings on chronic liver damage and liver cancer development. Liver cancer (hepatocellular carcinoma) developed in livers after chronic infection with Hepatitis-B and -C virus. Zender is heading a research group at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, and holds a professorship for experimental gastrointestinal oncology at the Hannover Medical School (MHH). He has pioneered the development of systems to conduct RNA interference screens in vivo. The award ceremony took place on Monday, 16th January, at the MHH.

Prof Lars ZenderProf. Dr. Lars Zender has received one of the most distinguished German cancer research awards. The Johann-Georg-Zimmermann Award, endowed with 10 000 Euro, highlights Zender’s findings on chronic liver damage and liver cancer development. Liver cancer (hepatocellular carcinoma) developed in livers after chronic infection with Hepatitis-B and -C virus. Zender is heading a research group at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, and holds a professorship for experimental gastrointestinal oncology at the Hannover Medical School (MHH). He has pioneered the development of systems to conduct RNA interference screens in vivo. The award ceremony took place on Monday, 16th January, at the MHH.


Another award, the Johann-Georg-Zimmermann Medal, endowed with 5 000 Euro, was given to Prof. Dr. Peter Krammer from the German Cancer Research Centre (DKFZ) in Heidelberg. Both awards are annually donated by the Deutsche Hypothekenbank. The Johann-Georg-Zimmermann Award distinguishes junior scientists for their current research projects, while the Johann-Georg-Zimmermann Medal recognizes the lifetime achievements of personalities in cancer research.
Prof. Lars Zender applies so-called RNA interference screens in order to find new cancer genes and therapeutic targets for the treatment of hepatocellular carcinoma. RNA interference is a complex mechanism that “silences” genes. This mechanism determines to a large extent, which genes – from the entire wealth of available genetic material – are finally active. Thus, RNA interference offers a new opportunity to intervene in the genetic regulation without manipulating the genes themselves. Together with only a few research groups worldwide Zender has developed the technical expertise to apply RNA interference and RNA interference screens in tumors of mice and to search for new therapeutic targets in the living organism. This method avoids problems that may occur when RNA interference screens are conducted in cultured cells of human tumors. New therapeutic targets that are identified by this method have a great potential to improve both the treatment and the prevention of liver cancer.
In 2009, Prof. Lars Zender accepted a professorship for gastrointestinal oncology at the MHH. Moreover, he supervises the project “Liver Regeneration” in the Excellence Cluster Rebirth, and he manages a project in the Collaborative Research Centre TRR 77 on Hepatocellular Carcinoma. Prof. Zender heads an Emmy Noether junior research group at the HZI and the MHH. He has already received numerous awards for his scientific research.
Prof. Peter Krammer was honoured with the Johann-Georg-Zimmermann Medal 2012 for his pioneering work on programmed cell death – so-called apoptosis. Apoptosis is the most frequent form of natural cell death in organisms. This mechanism removes cells that are no longer required for cell function or during embryogenesis, or contain defective genetic material. If this protective mechanism fails – resulting in too many or too few programmed cell deaths – diseases arise. A too low apoptosis rate is, for example, a central problem in cancer and autoimmune diseases. Prof. Krammer’s research work is regarded as a key to understanding the signalling pathways that regulate the mechanism of programmed cell death. Prof. Krammer is spokesman of the priority programme “Tumor Immunology” and heads the Department of Immune Genetics at the DKFZ in Heidelberg.

Further information:

Johann-Georg-Zimmermann Award and Medal:

Both awards are among Germany’s most traditional and best endowed research awards and are donated by the Deutsche Hypo Bank since 1972. Numerous German and international scientists have already been honoured. Professor Dr. Harald zur Hausen, winner of the Nobel Prize in Medicine, received the Johann-Georg-Zimmermann Medal 2006/2007.

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2012-01-31

Customized vaccine in a nasal spray format

HZI scientists investigate new approach to targeted activation and inhibition of defender cells

Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, are currently investigating Alpha-GalCerPEG, a substance capable of activating target groups of cells that are part of the body’s innate defense system. While many defense cells are activated by Alpha-GalCerPEG, T helper 17 (Th 17) cells are actually inhibited by it. Because uncontrolled activation of Th 17 cells can cause serious health problems, researchers are hopeful that they may be able to exploit Alpha-GalCerPEG’s unique ability to inhibit these cells at will, when required, in a wide range of settings. As such, Th 17 cells are strongly activated by the intranasal application of vaccines. Alpha-GalCerPEG was shown to be effective at inhibiting Th 17 cells, even when administered intranasally as an adjuvant.

SchnupfimpfungScientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, are currently investigating Alpha-GalCerPEG, a substance capable of activating target groups of cells that are part of the body’s innate defense system. While many defense cells are activated by Alpha-GalCerPEG, T helper 17 (Th 17) cells are actually inhibited by it. Because uncontrolled activation of Th 17 cells can cause serious health problems, researchers are hopeful that they may be able to exploit Alpha-GalCerPEG’s unique ability to inhibit these cells at will, when required, in a wide range of settings. As such, Th 17 cells are strongly activated by the intranasal application of vaccines. Alpha-GalCerPEG was shown to be effective at inhibiting Th 17 cells, even when administered intranasally as an adjuvant. These discoveries made by the Braunschweig researchers and published in the current issue of the scientific journal “PLoS ONE,” shed new light on Alpha-GalCerPEG’s considerable potential in the field of medicine.

Ideally, the entry of an infectious agent into a host organism will result in the activation and amplification of specific cells of the immune system capable of effectively protecting the host against the infectious agent. Vaccinations seek to mimic this effect in a controlled setting by purposely introducing attenuated pathogenic agents or their parts into a person’s body in order to trigger an immunological response without producing the disease state or its associated symptoms. The goal is to establish an immunological memory against the specific pathogen. The nature of the pathogen determines which defense cells the body will ultimately make and the extent of cell activation. Immune stimulation can also wreak havoc in the body, for example in situations where cells hyper-react causing collateral damage to bystander cells or body tissues, thereby triggering an unchecked acute or chronic inflammatory response.

Th 17 cells, discovered only a few years ago, are integral to the body’s innate ability to defend itself against many different pathogens. During the early stages of an inflammatory response, Th 17 cells act as vitally important antimicrobial “protection units." At times, however, Th 17 cells can steer the immune response in the wrong direction, which can result in states of chronic inflammation with tissue damage. Professor Carlos A. Guzmán, head of the Department of Vaccinology at the HZI Braunschweig, explains that for example “Th 17 cells have been implicated in the etiology of the arthritis observed following experimental infection with the bacterium Borrelia.” In contrast, the stimulation of Th 17 cells seems to be important to achieve protection against other infections, such as tuberculosis.

Although, to date, our understanding of Th 17 cells is still – at best – rudimentary and even though these cells are probably more helpful than harmful by defending our bodies against infections, Guzmán is convinced that “in many instances, it would be ideal if we could just switch off the Th 17 cells whenever we wanted to, without compromising the jobs of the other defenders.” While for vaccines that are administered intranasally proper measurement of the appropriate dose can prove difficult, the benefits, including for one the ease of administration, beg for more work to be done in this area and represent an important part of Guzmán's research. “If you use a nasal spray to administer a vaccine, you eliminate the need for unpleasant injections," explains Guzmán. One major downside is that "with the nasal spray vaccine Th 17 cells always tend to become very strongly activated.” The ability to “switch off” the Th 17 cells through the addition of Alpha-GalCerPEG to the nasal spray may be the solution, where required.

“Alpha-GalCerPEG's mechanism of action has been pretty well characterized at this point, an important step towards its controlled medical application,” comments Sebastian Weissmann, a scientist on Guzmán’s team. “One of the goals of our lab is to develop an immunological toolbox, which would allow us to combine individual molecular building blocks to elicit a custom-tailored immune response by vaccination against specific pathogens. With Alpha-GalCerPEG we have found one novel, promising building block.”

 

Original Publication:

NKT Cell Stimulation with α-Galactosylceramide Results in a Block of Th17 Differentiation after Intranasal Immunization in Mice. 

Beata M. Zygmunt, Sebastian F. Weissmann, Carlos A. Guzman

PLoS ONE

dx.plos.org/10.1371/journal.pone.0030382

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2012-02-10

Targeting the bacterial protective shield

Research consortium set on developing new drugs that target bacterial biofilms

Slime-like and near impenetrable are biofilms built by a number of bacterial cells during the course of an infection. Typically, they are composed of long molecular strands called polymers. Many different species of bacteria, among them dangerous pathogens like Pseudomonas and Staphylococcus, use biofilms to shield themselves against the host's immune system attacks and antibiotics' pharmacological mechanism of action. In Germany alone, 100,000 infections annually are related to bacterial biofilms. A joint research initiative by the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, and the TWINCORE, Centre for Experimental and Clinical Infection Research, aims to target bacterial biofilms using Nature's own list of active ingredients.

 Bakterieller BiofilmBacterial BiofilmSlime-like and near impenetrable are biofilms built by a number of bacterial cells during the course of an infection. Typically, they are composed of long molecular strands called polymers. Many different species of bacteria, among them dangerous pathogens like Pseudomonas and Staphylococcus, use biofilms to shield themselves against the host's immune system attacks and antibiotics' pharmacological mechanism of action. In Germany alone, 100,000 infections annually are related to bacterial biofilms. A joint research initiative by the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, and the TWINCORE, Centre for Experimental and Clinical Infection Research, aims to target bacterial biofilms using Nature's own list of active ingredients.

The project, funded by the German Federal Ministry for Education and Research (BMBF), is coordinated by the pharmaceutical company Sanofi. Further research affiliates are the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Germany, the Leibniz University Hanover (LUH), Germany, and the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM).


Biofilms represent a serious medical dilemma. The ones that result from bacterial infections and are not treatable are often responsible for the necessary replacement of knee and hip joint prosthetics and of artificial heart valves. Patient risks are often substantial, and costs are high. Serious illnesses like endocarditis, cystic fibrosis, or chronic obstructive pulmonary disease (COPD), in which biofilms play a central role, are often fatal because – to date – no drug exists that is capable of preventing biofilm formation or promoting biofilm dissolution.
An important focus of the initiative is the planned introduction of the first ever official biofilm inhibitor into the preclinical trial stage. The research is supported by grants in the total amount of 7.2 million euros. Half of this amount has been granted by the BMBF; the balance is contributed by Sanofi.


The scientists involved may very possibly find answers by turning to Nature’s own resources: together, Sanofi and HZI own one of the most extensive – and one of the most promising – collections of microorganisms and of chemical compounds that have been isolated from these. The substances' biofilm dissolving potential is to be characterized using a novel and unique biofilm test.
"We have developed a systematic test protocol that will enable us to qualitatively and quantitatively examine different substances for their biofilm inhibitory effect," explains Professor Susanne Häußler, HZI and TWINCORE work group leader. The most cutting-edge experimental techniques like automatic confocal microscopy are being used for the optic screening procedures. Besides searching for candidate active ingredients using in-depth screenings, the researchers are also hoping to investigate the formation and potential drug targeting of biofilms in the bodies of mice as part of the research initiative. "What makes our project especially promising is our ability to uniquely combine our screening protocol with a murine model; the fact that neither has previously been available to us is what has largely prevented the development of biofilm inhibitors," explains Häußler.


Scientists at HIPS, HZI's satellite facility, have, under Professor Rolf Müller's leadership, developed a pre-screening protocol to allow them to limit – for now – the vast range of candidate natural substances. "At this point, we are hopeful that we may be able to identify candidate substances that can be optimized for clinical development rather quickly," says Müller. For the time being, however, the pathway to actually developing a new drug using these substances as active drug ingredients still lies in the very distant future.

2012-02-20

Dangerous bacterium gets cold feet

Helmholtz scientists disarm plague pathogen's next of kin

In medieval Europe, the Black Death once decimated large parts of the population. Although in Europe no longer a genuine cause for concern, in Africa, South America, and India the Bubonic plague still to this day poses a viable threat to public health. The culprit behind the pandemic is a bacterium of the genus Yersinia. Each year in Germany, the pathogen's slightly less virulent relative is responsible for causing several thousand cases of diarrheal disease – often times with serious consequences. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, working closely with their colleagues at the Ruhr University in Bochum, Germany, have identified a mechanism that enables these bacteria to turn on their weaponry once inside the host. It turns out that Yersinia possesses a built-in molecular thermometer that jump-starts the bacterial pathogenic program at precisely 37 degrees Celsius, which corresponds to normal human body temperature.

Yersinia PseudotuberculosisDr. Manfred RohdeIn medieval Europe, the Black Death once decimated large parts of the population. Although in Europe no longer a genuine cause for concern, in Africa, South America, and India the Bubonic plague still to this day poses a viable threat to public health.  The culprit behind the pandemic is a bacterium of the genus Yersinia. Each year in Germany, the pathogen's slightly less virulent relative is responsible for causing several thousand cases of diarrheal disease – often times with serious consequences. Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, working closely with their colleagues at the Ruhr University in Bochum, Germany, have identified a mechanism that enables these bacteria to turn on their weaponry once inside the host. It turns out that Yersinia possesses a built-in molecular thermometer that jump-starts the bacterial pathogenic program at precisely 37 degrees Celsius, which corresponds to normal human body temperature.

By inducing genetic mutations in the bacterium, the researchers have successfully managed to reset the thermometer to a lower temperature setting, thereby permanently disabling the bacterial disease-causing program. The next step now is to identify a substance capable of inducing these modifications and administer it, alongside traditional antibiotics, in the form of a drug as part of the general treatment plan.


The scientists used as their model organism Yersinia pseudotuberculosis, the plague pathogen's next of kin. In Germany, this bacterium mainly infects young children - most commonly through ingestion of raw or undercooked pork. "Upon entry, the change detected in the external temperature informs the bacterium that it is now inside the human body," explains Dr. Katja Böhme of the HZI Department of Molecular Infection Biology. "Using special surface receptors, Yersinia attaches itself to cells in the small intestine, thus forcing its entry into the underlying tissue," adds her colleague Rebekka Steinmann. Once the bacterium has successfully entered into the tissue, it switches on its own pathogenic program to produce factors that shield the bacterium from attacks leveled against it by the human immune system and even kill off immune system cells. The bacterium's molecular thermometer acts as the switch. Outside the host’s body the regulator YmoA blocks the bacterium's anti-immune program. At body temperature, YmoA is inhibited, which jump-starts Yersinia's anti-immune programand readies the bacterium for attack. As a part of that program the gene encoding the chief regulator in charge of a wide range of pathogenic factors called LcrF is activated.


On the road to every cellular gene product, including Yersinia's multi-purpose weapon LcrF, the first step is the polymerization of a strand of mRNA, the molecular template and mobile transcript of a gene that the cell's protein synthesizing machinery can attach to. In the case of LcrF, however, if the strict temperature requirement of 37 degrees Celsius is not met, the mRNA template folds on itself and becomes tangled up, thus becoming useless and inaccessible for protein production. The consequence being that the bacterium's disease-triggering program remains switched off.


"We managed to interfere with LcrF's thermosensory control mechanism on two levels at once," explains Böhme. "First, we artificially increased the amount of YmoA, thus inhibiting expression of the gene coding for LcrF."  This alone, however, proved not nearly enough to inactivate the whole pathogen as the researchers still detected some level of LcrF activity that they were able to trace back to previously assembled LcrF mRNA molecules still present in the bacterial cell. Computer simulation of the mRNA molecules documented the existence of certain regions within its structure that are important for molecular folding and unfolding. "We next switched out individual building blocks within the LcrF template, so that the molecule was now incapable of unfolding and thus remained in a state of inactivation even at the proper temperature setting of 37 degrees. This successfully interfered with the bacterium's ability to start up its anti-immune program, thus giving the immune system a chance to eradicate it," explains Steinmann.


Prior to this research, molecular thermometers have only been described in the context of a cell's adjustment to heat stress, but not as the control mechanism behind important pathogenic genes, where they are a new discovery. "This opens up a whole new approach to fighting infections," explains Professor Petra Dersch, head of Molecular Infection Biology at HZI. "A molecule that can hold strands of LcrF mRNA together like a molecular clothespin of sorts, preventing it from unfolding and becoming active, would basically inactivate Yersinia and surrender it to the immune system. In addition, such a molecule, because it specifically targets pathogenic Yersinia, would also be an effective weapon in our fight against the Bubonic plague."


A common dilemma in the ongoing fight against infectious diseases is the constant and rapid genetic mutation of many pathogens. This explains why researchers today are always on the lookout for universal weak spots – properties or mechanisms that are central and indispensible to the pathogen's ability to cause disease in the host. "Our goal is to take out pathogens without eliminating useful bacteria in the same sweep, a common problem with current antibiotics." According to Dersch, "molecular thermometers in charge of a pathogenic bacterium's degree of virulence represent ideal targets."



Original Publication:
Böhme K, Steinmann R, Kortmann J, Seekircher S, Heroven AK, Berger E, Pisano F, Thiermann T, Wolf-Watz H, Narberhaus F, and Dersch P (2012): Concerted actions of a thermo-labile regulator and a unique intergenic RNA thermosensor control Yersinia virulence. PLoS Pathogens, February 2012, Volume 8, Issue 2, e1002518.

2012-02-23

Access to Hightech Infrastructure all over Europe

New Alliance “Instruct” connects cutting edge technologies across the borders

 

 Abbildung einer Protein Sample Production FacilityArbeitsgruppe Joop van den HeuvelMaking the most advanced technologies available to researchers all over Europe is the goal of the initiative “Instruct”. Fifteen research institutes from eight countries have launched this cooperation today in Brussels. Many more are supposed to follow and further broaden the shared technological basis. The HZI and four other German institutes are part of this alliance.

 

Instruct’s main focus is structural biology, a scientific discipline aiming to resolve the three-dimensional structure of biological molecules. The structure provides important insights into the biological function of these molecules, which in turn may lead to new concepts in understanding and fighting diseases.

 

The central hub of the Instruct network is the website www.structuralbiology.eu. This platform provides access to high-end technologies which most single research groups could not afford. Examples are highly specialized cell culture methods for protein expression housed at the HZI as well as newest imaging technologies like cryo-electron tomography or the use of electron accelerators for the analysis of molecular structures.
Further information at: www.structuralbiology.eu

 

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2012-03-02

Why Immune Stem Cells Disappear As We Age

German scientists illuminate underlying mechanism

With advancing age, a person's immune system often grows weaker. One reason behind this is the gradual decline of the stem cell population that the body draws on in its ongoing effort to replace old worn-out or damaged immune cells. Now, scientists at the University of Ulm, Germany, in collaboration with the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany, have at last identified the mechanism underlying age-related immune function loss. Although it takes place in all cells of the body throughout a person's life, the accumulation of DNA damage in certain blood stem cells activates a gene critical for their differentiation into mature defender cells - a process, which compromises the stem cells' capacity for continuous, lifelong self-renewal, and ultimately responsible for their loss. The researchers' findings are published in the renowned scientific journal Cell and are in fact the current issue's cover story.

T-ZellenStimulation of T cells by DC_1.Adult stem cells are found in almost all of the adult body's tissues.  Throughout a person's life, these cells, which, by definition, have not yet fully specialized, contribute to tissue renewal while retaining their ability to continuously replenish their own population.  For example, throughout the lifespan, hematopoietic stem cells in a person's red bone marrow continuously produce the cellular components of the blood. These include red blood cells but also white blood cells like the lymphocytes of the immune system.  It has been well established that, as we age, our hematopoietic stem cells lose their ability to give rise to the cells and cellular fragments of the blood - especially to those cells that make up our immune system, which helps defend our bodies against disease-bearing pathogens.

 

Now, the Max-Planck-Research Group on Stem Cell Aging at the University of Ulm, headed by Professor Lenhard Rudolph, has identified the mechanism underlying age-related immune stem cell loss.  Stem cells are among those cells in the human body with the greatest longevity record.  However, as the body ages mistakes accumulate in its stem cells' genetic material - their DNA.  "Our work shows that this age-related DNA damage promotes stem cell differentiation," Rudolph explains.  "This, then, is how the stem cells lose their capacity for continued self-renewal, and explains why and how their population is ultimately decimated."  It seems that those bone marrow stem cells in charge of renewing the immune system's B and T lymphocyte population are particularly susceptible and are rapidly lost as a direct result of age-related DNA damage.

 

The researchers used a highly specialized form of RNA interference technology (RNAi) available at HZI Braunschweig to study the molecular specifics underlying this process.  The technology allows for the targeted and highly effective 'knockdown' of individual genes of interest in a model organism.  Genetic screening protocols based on this technology allowed researchers in Professor Lars Zender's lab at HZI to directly examine a gene's effects in the tissues of mice.  "As part of this project we targeted and blocked individual genes in murine hematopoietic stem cells and examined how the suppression of gene function affected cell aging," explains Zender, who is also Professor at the Hanover Medical School (MHH).  Their results showed that a gene called BATF appears to play a key regulatory role in the stem cell aging process.  If BATF's transcription is being suppressed, the hematopoietic stem cells live longer; if, by contrast, BATF becomes expressed, cellular DNA damage results.

 

The newly identified mechanism is not only important as it helps explain the deteriorating immune system function seen in old age, but, as Rudolph proposes, "it is conceivable that this mechanism's primary function may be to protect the body against the development of certain types of cancer."  As such, the successful elimination of damaged stem cells from the body may prevent cancer development in early adulthood, as mutated stem cells are essentially 'filtered out' of the system.  On the other hand, an accumulation of DNA damage can lead to other problems later on in life, as insufficient numbers of functional stem cells are available for critical immune system maintenance.

 

Ulm's Jianwei Wang, who is first author of the study he worked on for his dissertation, is already thinking one step ahead: "If we were able to increase the lifespan of stem cells of the immune system - albeit without completely losing control over DNA damage - then we could potentially improve immune function in older adults - which means better overall protection against life-threatening infections."

 

Original publication:

A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage. Cell, Vol. 148, Issue 5, 1001–1014, March 2, 2012.

 

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2012-03-29

The Achilles' heel of cancer cells

University and HZI researchers discover many tumor cells cannot survive without the presence of an enzyme known as 'Ark5'

Scientists at Germany's University of Würzburg along with their Braunschweig colleagues at the Helmholtz Centre for Infection Research (HZI) recently discovered the existence of a weak link in certain types of cancer cells that may prove a promising target for novel kinds of drug treatments in cancer therapy. The pharmaceutical industry has already expressed an interest in the discovery. The researchers' findings are featured in the current issue of the renowed scientific journal Nature.

Like all body cells, cancer cells are dependent upon a continual supply of nutrients to allow them to generate the energy needed to power their various metabolic processes.  At the same time, however, they use up a large chunk of these nutrients for assembly of new cellular building blocks, cellular division, and proliferation.  Because a cell's nutrient supply is finite, each cell contains, if you will, its own 'security guard' in charge of always making sure that plenty of resources are at hand to support the different activities the cell must perform.  If the energy supply required to power everyday cellular activities becomes depleted, the security guard responds by limiting cellular growth.

 

Professor Martin Eilers and Dr. Daniel J. Murphy - both of the University of Würzburg's Biocenter - along with an international team of researchers recently set out to investigate what happens when a cancer cell's security guard is deliberately taken out of commission. Gewebeschnitt aus einem LebertumorDANIEL MURPHYTissue section from a liver tumorThe results showed that "if a cancer cell no longer receives feedback about the fact that its energy balance is out of whack, it will waste all of its resources on cellular growth and division," explains Martin Eilers, Professor and Chair of Biochemistry and Molecular Biology at the University of Würzburg.  In the process, the cell over-exerts itself to the point where no more energy is left for powering its everyday metabolic cellular activities.  In fact, as the research showed, without heeding its security guard's 'warning call' the cancer cell quickly dies.

 

It was by pure chance that the researchers ended up stumbling upon this cellular security guard.  In a series of experiments they switched off different enzymes in cancer cells called kinases and watched and analyzed the cells' response.  In the case of the kinase enzyme 'Ark5' they scored a slam-dunk.  "This particular kinase turned out to be the ideal target for potential new drug treatments," explains Daniel J. Murphy of the University of Würzburg's Department of Physiological Chemistry II.  Their experiments showed that Ark5 is a genuine 'weak link' in cancer cells.  Working closely with HZI Professor Lars Zender and his team, the researchers specifically inactivated the gene coding for Ark5 kinase in liver tumor cells of mice.  "This allowed us to demonstrate that when Ark5 gene expression is being suppressed in tumor cells, the tumor shrinks and the mice end up living longer," explains Zender. 

 

To the researchers' great surprise the experiments also showed that normal cells remain largely unaffected by targeted kinase inhibition.  "We don't yet fully understand every last detail behind this observation," Murphy concedes.  Potentially, there could be some long-term effects here as well.  But, for the time being, "what matters most with respect to new drug design is that normal cells seem to respond differently to Ark5 inhibition than do cancer cells," says Murphy.  Whether or not new therapeutic approaches will come out of this, only time will tell.  So far, the method has proven effective both in the dish and in animal experiments - at least in the case of intestinal and liver cancer cells.  To what extent other types of cancer cells may also be driven to their deaths using this approach remains to be seen.

 

With the pharmaceutical industry having already taken a keen interest in these findings, a collaboration between the University, HZI, and the pharmaceutical companies is now only a matter of time.  However, the researchers are already warning against getting everyone's hopes up prematurely.  Many more research studies are needed before it can be ascertained that these findings could in fact translate into new approaches to cancer therapy.

 

Original publication:

Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Lidan Liu, Jannes Ulbrich, Judith Müller, Torsten Wüstefeld, Lukas Aeberhard, Theresia R. Kress, Nathiya Muthalagu, Lukas Rycak, Ramona Rudalska, Roland Moll, Stefan Kempa, Lars Zender, Martin Eilers & Daniel J. Murphy. doi:10.1038/nature10927

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2012-04-29

Direct access to desired genes

Study of natural compounds made simpler: Bacterial researchers develop improved DNA technique

Targeted exchange of DNA segments instead of tedious search: German and Chinese scientists have developed a technique for the direct isolation of genetic information from complex mixtures of different bacteria. Compounds produced by bacteria can often be used as pharmaceutics, for instance as antibiotics or chemotherapeutics. With the new method, they can be produced in the laboratory much easier than previously. The researchers describe this newly developed method in the journal Nature Biotechnology. 

The method is a joint achievement of researchers from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), a branch of the Helmholtz Centre for Infection Research (HZI) in Braunschweig, the Biotechnology Centre of the Technical University Dresden, the College of Life Sciences in Hunan/China and the company Gene Bridges in Heidelberg. Workgroups of Professors Rolf Müller, Francis Stewart and Youming Zhang were involved.

Agarplatte mit E. coliAgar plate with colonies of Escherichia coli bacteria. E. coli is used in order to produce natural products from other bacteria species.In addition to primary metabolism, which covers among other things the basic functions involved in housekeeping and reproduction, bacteria have also developed a number of secondary metabolic pathways. Products of these pathways are not essential for the survival of the bacteria, but help to improve adaptation to their environment. Many of these secondary metabolites are substances of pharmaceutical value. In order to characterize and analyze them for their potential medicinal application, researchers have to produce and isolate significant quantities of these compounds. Often it is difficult to harvest them from bacteria, as the exact conditions, under which the secondary metabolites are produced, are unknown. Thus scientists often isolate the genes, which are responsible for the production of the substance and transfer these to other bacteria that are easier to cultivate and produce the substance of interest. 

To date, scientists have used a so-called DNA library for this task, which contains the whole genetic information of an organism as small pieces. After creation of a library, researchers had to screen it for the candidate gene. If a complete copy was present, they would transfer it to a special small DNA molecule and implant it into the target bacterium. There was an additional obstacle for natural compounds: “Often, a larger number of genes, so called gene clusters, are needed for the production of secondary metabolites. Their isolation is rather difficult”, explains Rolf Müller, director of HIPS and head of the department of Microbial Natural Products. 

In the age of massive parallel DNA sequencing, the complete genomes of many bacteria are already known, and with them theoretically thousands of pathways for secondary metabolites. With the help of the newly described method of so-called “direct DNA cloning” genes for secondary metabolites can specifically be isolated and processed. The long detour via the DNA library can be bypassed.

To achieve this, participating scientists Xiaoying Bian of HIPS and Jun Fu from the Biotechnological Centre of the Technical University of Dresden and their colleagues have improved the patented technology of homologous recombination: Certain enzymes can be used to exchange a gene segment for a different, similarly composed segment. If the order of the components at the beginning and at the end of the gene of interest is known, a similar segment can be constructed and exchanged enzymatically. In principle, this method is not novel. However the enzymes currently used, Red-alpha and Red-beta, are not efficient enough to employ this approach for the isolation of large DNA segments and hence do not allow the subsequent production of natural compounds in the lab. The researchers have now discovered that certain variants of the enzymes RecE and RecT work much better than Red-alpha and Red-beta.

“Improved direct cloning makes it much simpler and shorter to isolate and characterize interesting secondary compounds” says Xiaoying Bian, one of the first authors of the study from HIPS. “The huge effort to create and screen a DNA library is now obsolete.” HIPS director Rolf Müller adds: “Many pathogenic bacteria have become resistant against common antibiotics and therefore it is crucial to find new substances to target infections. Our approach allows us to make use of the available complete genome sequences of many microorganisms for the targeted search for new compounds.”

The researchers have already employed the simplified method for the direct transfer of several gene clusters from the luminescent bacteria Photorhabdus luminescens to Escherichia coli. In doing so, they have identified two previously unknown secondary metabolites, Luminmycin A and Luminmide A/B.

 

Although this recently published study aims to illustrate the possibilities of the method, it also raises hopes for the discovery of novel natural compounds that can be used as antibiotics and thus lead to continued progress in fighting infectious diseases.

Original Publication:

Jun Fu, Xiaoying Bian, Shengbaio Hu, Hailong Wang, Fan Huang, Philipp M Seibert, Alberto Plaza, Liqiu Xia, Rolf Müller, A Francis Stewart & Youming Zhang (2012) Full-length RecE enhances linear-linear homologous recombination and facilitates direct cloning and bioprospecting, Nature Biotechnology, 30, 440-446.

 

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2012-05-02

HZI opens study centre in Hannover

Long term medical studies of chronic diseases planned

Frontansicht des Clinical Research Center HannoverFront View of the Clinical Research Center HannoverThe new premises of the HZI study center in Hannover have been opened with an official ceremony today.

In the future, long-term population studies with voluntary probands will be conducted in the new centre. The results are supposed to shed new light on chronic diseases such as cancer or dementia. “We want to study how currently neglected factors, among them infections, influence the risk to develop these severe illnesses”, explains Prof. Gérard Krause, head of the HZI department of Epidemiology, which is running the study center. Contributions of the HZI study center to larger Germany-wide health studies are planned.

The study centre will reside in the now opened rooms in Feodor-Lynen-Str. 5 for the time being. Later it will move into the neighboring Clinical Reserach Center Hannover (CRC), which is still under construction

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2012-05-15

HZI awards young infection researchers

The Jürgen Wehland Prize – endowed with 5000 Euros – is announced / application deadline 1 July

Fahnen HZI
 Ansicht vom HZI mit Fahnen im Vordergrund Fahnen HZI Ansicht vom HZI mit Fahnen im VordergrundFor the second time, the Helmholtz Centre for Infection Research (HZI) in Braunschweig and the Friends of the HZI support young scientists with an award in memory of the former Scientific Director of the HZI, Professor Jürgen Wehland.

The Jürgen Wehland Prize includes prize money of 5,000 Euros and will be awarded on 7 September, 2012. The award ceremony will take place during the scientific symposium “NORDI”, which will be held in honour of Wehland www.helmholtz-hzi.de/nordi.

The call is aimed at young scientists with research focus on infection biology. Their doctorate should not date back longer than five years; parental leave will be taken into account. The applicants should currently work in a German-speaking region, preferably in Northern Germany, or have performed their work in this region.

Personal applications are possible as well as suggestions from a supervisor or superior. Please send your application in one PDF file via email.
Application requirements:
1. Short description of research (1 page)
2. CV
3. list of publications
4. brief assessment of the research by an established scientist (1 page)
5. contact addresses of the candidate and the assessing scientist
6. one to a maximum of three publications that emerged from the work
Please send the documents via email to juergen-wehland-preis@helmholtz-hzi.de until 1 July, 2012.

 

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2012-06-14

Search for germs in Braunschweig residents’ noses

Helmholtz Centre for Infection Research launches study of multiresistant bacteria

NasentupferHZIA nasal swab is painless and can be performed by the probands themselves.In the next few days, two-thousand randomly selected citizens of Braunschweig will receive mail from the Helmholtz Centre for Infection Research (HZI). In this letter they will be invited to participate in a public health study. Scientists from the Department of Epidemiology of the HZI want to investigate how frequently the bacterium Staphylococcus aureus occurs in the population. Twenty to thirty percent of the people carry this germ on the skin, in the nose or in the throat. Usually this goes unnoticed, as the bacterium is not harmful under normal circumstances. However, if the bacterium enters an open wound or if the host’s immune system is weakened, it can lead to dermatitis, pneumonia or even sepsis.

Why is this the case and why are only some people carriers of this pathogen? These are the questions the health researchers want to answer in the coming six months. “We are especially interested in staphylococci that are resistant to different antibiotics”, explains physician and molecular biologist Dr. Frank Pessler, who is leading the study in collaboration with the epidemiologist Dr. Manas Akmatov and the biostatistician Jaishri Mehraj. So-called multiresistant germs, first and foremost the “methicillin-resistant Staphylococcus aureus” (MRSA), have become more prevalent in the past few years and pose a growing threat to healthcare. As only a few antibiotics are effective against them, their treatment is tedious and long.

Participating in the study takes little effort from the volunteers, is completely painless and can be performed at home. At the beginning of the study, participants fill out a questionnaire and take a nasal swab, both of which are returned to the HZI. Over a period of six months, they receive monthly packages containing fresh swabs.

Pessler is asking citizens to participate: “It is crucial that as many people as possible take part. Only then can we gain important insights that may help us fight multiresistant germs more efficiently in the future. In the long run, all citizens will profit from this.” Besides the satisfaction of contributing personally to medical research, there is an additional benefit for participants: If Staphylococcus aureus is detected, the family doctor can decide whether treatment is advisable.  

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2012-06-21

Combined know-how in the fight against pathogens

27 June: “German Centre for Infection Research” is founded in Braunschweig / Press conference at 3.30 pm

InfektionsforschungResearch Laboratory32 leading research institutions from all over Germany combine their expertise: In future they want to team up to fight infections in the "German Centre for Infection Research" (DZIF). The registered association DZIF e.V. will be undertaking joint projects to obtain more detailed knowledge on pathogens that can be used to fight them and finally translate these findings into clinical applications. Representatives of the participating universities, hospitals and research centres will assemble on 27 June at the Helmholtz Centre for Infection Research (HZI) in Braunschweig to found the DZIF and elect its management board. The joint DZIF office will also be located at the HZI.

 

"Infectious diseases are one of the main causes of death worldwide," says Prof. Martin Krönke, Cologne, the current DZIF spokesperson. Time and again, new, unknown pathogens emerge, and since many bacteria have become resistant to our conventional antibiotics, the problem has become even more severe in recent years."

This is where the researchers involved in the DZIF want to specifically take countermeasures: Their aim is to use the combined know-how of the outstanding minds and a network of modern laboratory and analytical techniques to find approaches for new therapies, drugs, vaccines and vaccination methods. They will focus on so-called translation, the improved flow of findings and innovation from basic research into clinical application.

After it has been founded, the DZIF will start work on its mission almost immediately. The first projects have already begun: For example, translational research projects to develop novel treatment strategies against the long-term consequences of HIV infection will be relying on the expertise of the DZIF partner locations. "Basic research and clinical application work hand in hand here," says Prof. Hans-Georg Kräusslich, local coordinator of the DZIF in Heidelberg and Coordinator for the HIV research area. The DZIF places great emphasis not only on translational research but also on training. "The mission of the newly established DZIF Academy is to inspire young scientists and doctors for infection research and to provide them with the best possible tools for their career," says Prof. Ulrike Protzer from Munich, DZIF Academy coordinator.

 

The German Centres for Health Research

The DZIF is one component of the "German Centres for Health Research" concept with which the German Federal Ministry for Education and Research (BMBF) wants to push ahead in the fight against the most important endemic diseases.In addition to the DZIF, research collaborations for cardiovascular diseases, lung diseases and cancer have been established on the basis of expert recommendations. A German Centre for Diabetes Research and a German Centre for Neurogenerative Diseases were founded back in 2009.At the end of 2010, an international, independent panel of experts selected the highest performing institutions from a large number of applicants for the DZIF. "We are delighted that we can accommodate the DZIF here and support it with our infrastructure," says Prof. Dirk Heinz, Scientific Director of the HZI in Braunschweig. The HZI's scientific contribution will focus on drugs research in addition to its work on infection biology issues, explains Heinz.

 

Press conference at the Founding Meeting

There will be an opportunity to talk with leading representatives of the DZIF including the newly elected Board after the Founding Meeting on Thursday, 27 June, at 3.30 pm. We would like to ask all media representatives to register in advance with the HZI Press Office (+49(0)531-6181-1401, presse@helmholtz-hzi.de).

Partner locations of the German Centre for Infection Research (DZIF)

Bonn-Cologne
Rheinische Friedrich-Wilhelms-Universität Bonn
Universitätsklinikum Bonn
Universität zu Köln
Universitätsklinikum Köln

Gießen-Marburg-Langen
Justus-Liebig-Universität Gießen
Phillips-Universität Marburg
Paul-Ehrlich Institut, Langen
Technische Hochschule Mittelhessen

Hamburg-Lübeck-Borstel
Universität Hamburg
Universitätsklinikum Hamburg-Eppendorf
Bernhard-Nocht-Institut für Tropenmedizin (Leibniz Gemeinschaft)
Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie
Universität Lübeck
Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften

Hanover-Braunschweig
Medizinische Hochschule Hannover
Helmholtz-Zentrum für Infektionsforschung
Twincore - Zentrum für Experimentelle und Klinische Infektionsforschung
Stiftung Tierärztliche Hochschule Hannover
Leibniz-Institut DSMZ - Deutsche Sammlung von Mikroorganismen und Zellkulturen
Technische Universität Braunschweig

Heidelberg
Ruprecht-Karls-Universität Heidelberg
Universitätsklinikum Heidelberg
Deutsches Krebsforschungszentrum

Munich
Ludwig-Maximilians-Universität München
Klinikum der Universität München
Technische Universität München
Klinikum rechts der Isar der Technischen Universität München
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Institut für Mikrobiologie der Bundeswehr

Tübingen
Eberhard Karls Universität Tübingen
Universitätsklinikum Tübingen
Max-Planck-Institut für Entwicklungsbiologie

Contact person:

Dr. Timo Jäger

Tel. 0531 6181-2011
Fax 0531 6181-1499
presse@helmholtz-hzi.de

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2012-06-28

Lymphnode roundabout

Researchers probe origin of optimized antibodies against infections

An organism's ability to make new antibodies and use them to optimize its own immune defenses is of central importance in the fight against pathogens. In the case of severe infections, the overall relative speed with which an immune response proceeds could mean the difference between life and death. An international team of scientists, among them systems immunologist Prof. Michael Meyer-Hermann of the Helmholtz Centre for Infection Research (HZI) of Braunschweig, Germany, has now found that asymmetric division of antibody-producing B cells speeds up the body's immune defenses. Early on, one daughter cell starts making antibodies while the other works at refining its own antibodies. The researchers' findings are due to be published in the upcoming issue of the scientific journal, Cell Reports.

 

Division and selection of B cells inside germinal center of lymph node (computer simulation): Blue cells are in the process of dividing, while green cells are in the process of being selected. Grey…

 

Our immune system produces antibodies as effective long-term weapons against viral or bacterial infections or following vaccination. Antibodies are made in lymph nodes by specialized cells called B lymphocytes. In certain areas within a lymph node - called germinal centers - these B cells first undergo a process of selection.

B cells proliferate, mutate, and thereby change their antibodies. The immune system then checks to make sure whether or not these mutations translate into an improved immune response. If so, the cells in question are selected. The final outcome is the production of optimized antibodies capable of efficiently attaching to a particular pathogen and thereby inactivating it or labeling it for subsequent destruction by phagocytic scavenger cells. "As part of this evolutionary process, the immune system takes turns between chance mutations and best-candidate-selection," explains Michael Meyer-Hermann, Director of the HZI’s Department of Systems Immunology and professor of systems biology at the Technische Universität Braunschweig. "We are calling it the 'recycling hypothesis'." All of this allows the immune system to make sure that any antibody it produces is maximally effective against the particular pathogen it is looking to fight.

A year and a half ago, an international team of New York-based and HZI researchers described this process of antibody optimization experimentally in great detail. However, up until now, the nature of the trade-off relationship between mutation and selection was unclear. "There has been a lot of debate about whether or not one should picture this process as a one-way street or as a roundabout," says Meyer-Hermann. As the study's first author, Meyer-Hermann has analyzed his colleagues' experimental results mathematically and determined that the earlier measurements are only compatible with the idea of a roundabout.

At the beginning of the year, a team of British researchers from London showed that B cell division is asymmetric, resulting in production of unequal daughter cells. At first, the purpose of this kind of asymmetric cellular division seemed uncertain. Meyer-Hermann's analyses suggest that one of the two daughter cells leaves the germinal center and starts producing antibodies while the other stays behind and undergoes another round of mutation and selection inside the germinal center. The mathematical model illustrates the advantage of this type of set-up. While one fairly specialized daughter cell is already making antibodies, its clone, which can be further optimized in the next round, stays behind. Compared with symmetric division, in asymmetric division there is a tenfold increase in the number of antibodies produced. In addition, the cell that stays behind in the germinal center stores information regarding a successful antibody it has produced, and the optimization process thus concludes more quickly. "This kind of time-saving in antibody production can be a real life-saver in the case of a dangerous infection," explains Michael Meyer-Hermann.

 

The Department of Systems Immunology of the HZI, led by Prof. Michael Meyer-Hermann, addresses the mathematical modelling of immunological questions. It is part of the Braunschweig Integrated Centre for Systems Biology (BRICS), a joint research centre for systems biology founded by the HZI and the Technische Universität Braunschweig.

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2012-08-16

Virus throws a wrench in the immune system

Braunschweig researchers show long-term consequences of chronic virus infection

T cells are immune cells important for the defence against viruses. The on-going exposure to cytomegalovirus impairs their function. 
In the picture: Two T cells (red) interacting with a dendritic…HZI / M. RohdeThe cytomegalovirus (CMV) is a member of the herpesvirus family. Although most people carry CMV for life, it hardly ever makes them sick. Researchers from the Helmholtz Centre for Infection Research and from the USA have now unveiled long term consequences of the on-going presence of CMV: Later in life, more and more cells of the immune system concentrate on CMV, and as a result, the response against other viruses is weakened. These research results help to explain why the elderly are often more prone to infectious diseases than young people. 

 

The viral immunologist Professor Luka Cicin-Sain, head of the junior research group “Immune Aging and Chronic Infections” at the HZI in Braunschweig, Germany, and his colleagues have now published their discovery in the open access journal PLoS Pathogens. In the article, they describe that even months after infection with CMV, mice still show weaker responses against other viruses such as the flu virus.

Most adults are infected with CMV, yet this infection goes unnoticed. Usually that is of no consequence, because in the vast majority of cases, this herpesvirus does not make them sick. Only for people with a weak immune system, like organ recipients, AIDS patients, or unborn babies infected during pregnancy, the infection is dangerous. In everyone else, the virus becomes latent and persists in the body, but is kept at bay by the immune system. “In young people this lasting activation of the immune system might even be beneficial, because an active immune system may defeat other infections rapidly. But a bright candle burns down faster”, says Cicin-Sain, to clarify that the immune defence will wear out over the years. In elderly, the immune system loses function and its changes that present a clear loss of immune protection are summarily termed the “Immune risk profile”, shortly IRP. A relationship between IRP and the presence of CMV has been observed in several clinical studies. However, up to now it was unclear whether IRP is a consequence of the CMV infection or, vice versa, the IRP resulted in increased susceptibility to CMV infection.

The results of Cicin-Sain’s group and his American colleagues from the Oregon Health and Science University in Portland and from the College of Medicine of the University of Arizona in Tucson show that the on-going CMV presence contributes to immune ageing. “Of course the immune system ages without CMV as well”, Cicin-Sain explains. On the other hand, CMV is a permanent guest that demands a growing amount of attention from the T cells, an important group of immune defence cells. The longer the mice were infected with CMV, the more of these cells were engaged with the cytomegalovirus and were missing for the fight against other pathogens. Accordingly, the immune system of CMV-infected mice could not respond well to other infections, for instance to the flu- or the West-Nile-virus. “We believe that the large number of CMV-specific T cells in the lymph nodes is likely to impair the activation of the remaining cells”, the researcher concludes. What accelerated the immune defence in the young organism now becomes a burden in an old organism and takes its toll. Luka Cicin-Sain thinks a little further and summarizes: “Our results clearly show how important it would be to develop a vaccine against the cytomegalovirus, despite its low direct impact on human health.”

Original publication:

Luka Cicin-Sain, James D. Brien, Jennifer L. Uhrlaub, Anja Drabig, Thomas F. Marandu, Janko Nikolich-Zugich
Cytomegalovirus Infection Impairs Immune Responses and Accentuates T-cell pool Changes Observed in Mice with Aging
PLoS Pathogens, 2012, http://dx.plos.org/10.1371/journal.ppat.1002849

 

The group "Immune Aging and Chronic Infections" investigates the influence of pathogens on the aging of the immune system. To do so, the researchers are studying infection with cytomegalovirus (CMV).

2012-08-03

Natural substances halt bacterial growth

US scientists explain mechanism of action of substances discovered at HZI

Sorangium cellulosumElectron-microscopic photograph of cells of Sorangium cellulosum.The current issue of the renowned scientific journal Science features the story of an international team of researchers and their serendipitous discovery of a group of natural substances capable of limiting bacterial growth. The substances – first described at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, Germany – are inhibitors of RNA polymerase, the enzyme in charge of gene transcription in bacterial cells. Now, using highly sensitive analytic tools, scientists were at last able to demonstrate that these bioactive substances interfere specifically with the process of transcription by attaching to a site on the enzyme that is different from where traditional antibiotics normally attach – a property, which makes them very promising candidates in new drug design.

Myxopyronin, corallopyronin, and ripostatin are all different substances produced by a group of bacteria called myxobacteria. These microorganisms, which live in the soil, synthesize a number of biologically active chemicals. The antineoplastic properties of some of these chemicals, like epothilon, which was first discovered at HZI, make them effective agents in the fight against tumor cells – a property that has since been exploited in anti-cancer drug design. Others, like myxopyronin, corallopyronin, and ripostatin, are capable of killing off different types of pathogenic bacteria.

A number of years ago, HZI scientists had already begun to understand that these substances work by taking bacterial RNA polymerase out of commission. The specifics of this process have now been characterized as part of a collaborative research effort with Rutgers University in New Jersey, USA. It appears that the enzyme’s basic molecular shape resembles that of a crab’s claw. To attach the bacterial DNA, this "claw" must first be opened; once transcription has concluded, it closes up again. Myxopyronin, corallopyronin, and ripostatin all interfere with the opening of the enzymatic "claws," such that RNA polymerase essentially gets "stuck," remains closed, and is thus no longer capable of gene transcription.

Using the highly sensitive marker method "smFRET" – the acronym stands for "single molecule fluorescence resonance energy transfer" –, the US team, led by Richard Ebright and Anirban Chakraborty, was able to describe the exact distance between the two "tips" of the molecule’s "claw" during different stages of the transcriptional process, which has helped them elucidate the substances’ mechanism of action. 

"What makes our substances so remarkable is that they work differently from other, known antibiotics," explains HZI scientist Dr. Rolf Jansen of the Microbial Drugs Department. "Their application in the fight against those bacteria that have evolved resistance to traditional antibiotics opens up a world of possibilities in terms of new drug design."

Adds Jansen's colleague, Dr. Herbert Irschik: "The substances cannot in their current form be used as drugs quite yet. True – they have proven highly effective against bacteria in vitro. However, before their full effect on the human body can be characterized and their tolerance with patients determined, we have to first continue to fine-tune their integration into potential new drugs. At this point, it is too soon to say with certainty whether this will even be possible." Looking into this more is high up on the scientists' to-do list.

"Our findings point to myxobacteria's considerable potential vis-à-vis new drug design, and that of similar microorganismal natural substance producers," adds Prof. Rolf Müller, head of HZI’s Department of Microbial Natural Products. "A number of drugs, most commonly those used in the fight against infectious diseases, are nature-made. We are quite certain that we will discover a number of equally promising natural substances over the next few years."

HZI's Microbial Drugs Department is concerned with the investigation of microorganismally produced substances that can be medically exploited, such as for use as antibiotics. The team's primary focus is on a group of bacteria called myxobacteria.

Original Publication: 

Opening and Closing of the Bacterial RNA Polymerase Clamp Anirban Chakraborty, Dongye Wang, Yon W. Ebright, You Korlann, Ekaterine Kortkhonjia, Taiho Kim, Saikat Chowdhury, Sivaramesh Wigneshweraraj, Herbert Irschik, Rolf Jansen, B. Tracy Nixon, Jennifer Knight, Shimon Weiss, and Richard H. Ebright Science 3 August 2012: 591-595.

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2012-08-23

Experts on infection meet in Braunschweig

7 September: Jürgen Wehland Symposium - NoRDI III at HZI / Awards for junior researcher and renowned scientist

Staph aureus TeaserPathogens and their molecular “weapons“, mechanisms of immune defence, new therapies and agents against bacteria and viruses: this year’s program of the „North Regio Day on Infection“, in short “NoRDI”, offers a multitude of topics dealing with infection research. The expert meeting at the Helmholtz Centre for Infection Research (HZI) in Braunschweig will take place already for the third time on Friday 7 September. During the symposium, the Jürgen Wehland Prize and the Seeliger Prize will be awarded. 

 

“Infections are continually posing a substantial threat worldwide“, says Prof. Petra Dersch, microbiologist and head of the department “Molecular Infection Biology” at the HZI. “New pathogens emerge repeatedly and spread in epidemics around the world. Even the well-known pathogens are more and more difficult to combat as they have developed resistances against antibiotics.” 

Therefore scientists want to learn as much as possible about bacteria, viruses and their survival strategies and exchange their knowledge at an international level. This is the aim of visitors and speakers of the NoRDI III: Experts from leading research institutes in the United States, Sweden and Germany report on the latest findings from their scientific fields on 7 September. Topics cover dangerous pathogens like legionella, the influenza virus and the tubercle bacteria as well as the correlation between infections and cancer.

On the occasion of the meeting, the HZI will award the Jürgen Wehland Prize to honour an outstanding junior scientist in memoriam of the former Scientific Director of the HZI.  For the first time, also the Heinz-P. R.-Seeliger Foundation will award the Seeliger Prize as part of the NoRDI meeting. Both prizes are endowed with 5 000 Euros.

“The NoRDI meeting offers young scientists, especially from Northern Germany, the possibility to meet internationally renowned infection researchers face-to-face”, says Prof. Dirk Heinz, Scientific Director at the HZI. “We are proud to host such an event in Braunschweig.”

 

For application, program and further information, please visit:

www.helmholtz-hzi.de/nordi

 

NoRDI

The „North-Regio-Day“ on Infection“ (NoRDI) was established in 2010 as a central event and meeting place for scientists from universities and research institutes of the North Regions of Germany to exchange new research results, recent technical developments and to discuss important questions and future tasks in different fields of infection biology. NoRDI is coordinated by the HZI, the Technische Universität Braunschweig, the Robert Koch Institute Wernigerode and the Twincore and is sponsored with funds from the Ministery for Science and Culture of Lower Saxony and the Robert Koch Institute. No participation fee is required.

 

The Jürgen Wehland Prize

The Jürgen Wehland Prize of the HZI, which is endowed with 5 000 Euros, is awarded every year on the occasion of the NoRDI meeting. It honours outstanding junior scientists focusing on infection biology. The prize is named after the former Scientific Director of the HZI, Prof. Jürgen Wehland. 

 

The Seeliger Prize

This Prize is named after Prof. Dr. P. R. Seeliger, who held the chair in Hygiene and Microbiology at the University of Würzburg from 1965 to 1989. He was one of the internationally most known German microbiologists and is considered to be one of the pioneers in listeria research. In order to promote microbiological research, his widow Brigitte Seeliger-Wagner established the Seeliger Foundation in 1998.

2012-09-03

Drug researchers’ valuable “bycatch“

Bacterial eliamid inhibits tumor cells

Sorangium cellulosumHZIThe natural substance eliamid is capable of suppressing cancer cell proliferation – so far in the test tube. Produced by certain strains of soil bacteria, the substance was re-cently characterized by a group of scientists at the Helmholtz Centre for Infection Re-search (HZI) in Braunschweig, Germany. Now, Dr. Evgeny Prusov and his team are sharing their insights into why they consider eliamid a potential candidate for drug development and how synthetic versions of it might be "created" in the lab, in the sci-entific publication "Chemistry – A European Journal."

 

As one of their long-term effects, certain infectious diseases can cause cancer. As such, the hepatitis B virus, for example, is known as a potential trigger of hepatic cancer. In 2008, the scientists who first documented the connection between certain viruses – such as HPV, the human papilloma virus – and cervical cancer were awarded the Nobel Prize in Physiology or Medicine. Although vaccines can effectively afford protection against these two viruses, the need to find new active compounds to fight cancer persists. 

One such potential candidate substance is the newly discovered bacterial eliamid. When examining its biological activity, eliamid stood out for its antifungal, and, most remarkably, anti-proliferative effects on a number of different cancer cell lines. Back in the 1980s, Braunschweig scientists had already discovered another nowadays im-portant substance, epothilone, a secondary metabolite synthesized by certain bacterial strains. Epothilone has been successfully developed into an anti-breast-cancer drug and marketed in the US since 2007.  

The soil-dwelling bacterium Sorangium cellulosum belongs to the order of myxobacteria. Myxobacteria produce a plethora of secondary metabolites – substances that are not vital to bacterial survival but can bestow a certain evolutionary advantage on them over competing species. For that reason some of these substances have antibiotic properties, whereas others seem better suited to tumor therapy. In fact, a number of HZI scientists have focused their research on identifying such medically useful substances. 

And in the process, Evgeny Prusov and his team discovered eliamid’s potential anti-cancer activity practically by accident. "What we were actually looking for were natu-ral substances that could be developed into novel antifungal drugs," explains Dr. Klaus Gerth of HZI’s Department of Microbial Drugs, one of the study’s co-authors. "We only discovered eliamid serendipitously when we analyzed two strains of Sorangium cellulosum, a bacterial species, which produces antifungal substances." However, upon closer inspection we found that, in the test tube, eliamid inhibited cellular proliferation of both cervical cancer cells and lymph node ulcers, at a comparatively low-level toxicity. And just as a fisherman would not discard a valuable bycatch back into the sea, the researchers immediately realized the potential of this promising by-product.

It will be a few more years, however, before eliamid may help treating cancer patients. Between epothilone’s discovery and the point where it finally hit the market, two whole decades had come and gone. "The continued development of a natural substance into a drug is extremely time-consuming”, Prusov explains. "First, we need to do a lot more work with eliamid and also figure out how to produce derivatives" – slightly modified variants with enhanced efficacy and selectivity. The additional steps towards creating a mature drug would then be taken by a pharmaceutical company, as the process is far too costly and time-consuming for a research institute. But Evgeny Prusov is confident: "If our eliamid can one day help treat or cure a sick person, that would be an especially rewarding success of our research."

Original publication:

Gerhard Höfle, Klaus Gerth, Hans Reichenbach, Brigitte Kunze, Florenz Sasse, Edgar Forche & Evgeny V. Prusov
Isolation, Biological Activity Evaluation, Structure Elucidation, and Total Synthesis of Eliamid: A Novel Complex I Inhibitor 
Chem. Eur. J. 36/2012

2012-09-07

Influenza researcher awarded with Jürgen Wehland Prize

Stephanie Bertram receives prize for junior scientists by the Helmholtz Centre for Infection Research

Stellvertretend für die erkrankte Preisträgerin nahm Stefan Pöhlmann, Leiter der Abteilung Infektionbiologie des DPZ, die Auszeichnung entgegen.  
Im Bild: Dirk Heinz, Wissenschaftlicher…HZIStellvertretend für die erkrankte Preisträgerin nahm Stefan Pöhlmann, Leiter der Abteilung Infektionbiologie des DPZ, die Auszeichnung entgegen. Im Bild: Dirk Heinz, Wissenschaftlicher Geschäftsführer des HZI, Stefan Pöhlmann und der Laudator Stephan Becker (v.l.n.r.). On 7 September, Dr. Stephanie Bertram, scientist at the German Primate Centre, was bestowed the Jürgen Wehland Prize. This honour acknowledges her outstanding research on influenza viruses and new therapies. The award ceremony took place during the third “North-Regio-Day on Infection”, briefly NoRDI III.

 

Every winter, when more people fall ill with flu, the causative agent, the influenza virus, is in the spotlight. Besides the seasonal influenza, pandemic influenza also emerges repeatedly: As influenza viruses change constantly, a virus may arise that only few people are immune against. “Current drugs target virus structures which change very fast during therapy. As a consequence, resistant viruses originate”, describes Stephanie Bertram the disadvantages of present therapies. Her research might now contribute to new influenza therapies circumventing the development of resistances. She and other scientists discovered that the process of infection not only requires virus molecules. Also some of the body’s own molecules, the so-called type III transmembrane serin proteases, are essential for effective infection. These molecular machines activate an important virus protein and make the influenza virus infectious. Bertram demonstrated that they occur in cells that are usually attacked by the viruses. She has thus found a component of the infection process that does not change as fast as the virus molecules. This opens up new possibilities in the therapy of diseases caused by viruses: Drugs targeting the body’s own, but dispensable molecules will not induce viruses to become resistant. The laureate feels encouraged by the appreciation: “To receive the Jürgen Wehland Prize is a big honour for me as a young scientist. It is also an acknowledgement for my research and motivates me to further study the fundamentals of virus-host cell interaction”, says Stephanie Bertram.

Bertram studied biology in Braunschweig and Hamburg. She focused on influenza viruses already during her PhD thesis at Hannover Medical School and continues to study them and their activation as a postdoc at the German Primate Centre in Göttingen.

The Jürgen Wehland Prize is awarded for the second time by the HZI and the Friends of the HZI. It acknowledges outstanding scientific achievements of young scientists. The prize, which is endowed with 5 000 Euros, is named after the former Scientific Director of the HZI, Prof. Jürgen Wehland, who very much supported young researchers. 

The “North-Regio-Day on Infection“ (NoRDI) was established in 2010 for scientists from universities and research institutes of Northern Germany to exchange new research results and recent technical developments. Today, the  event also attracts interest beyond the region. It offers particularly young scientists the possibility to discuss their research with renowned infection researchers.

 

For further information, please visit:

www.helmholtz-hzi.de/nordi

 

2012-09-13

Das HZI bekommt Nachwuchs

Drei junge Wissenschaftler starten Anfang 2013 eigene Forschergruppen am HZI

ImpressionenImpressionenMarc Erhardt, Till Strowig und Alexander Titz haben sich in einem strengen Wettbewerbsverfahren durchgesetzt und werden nun mit jeweils 250.000 Euro über fünf Jahre gefördert. Sie werden am Helmholtz-Zentrum für Infektionsforschung (HZI) forschen und sich an der Lehre an Partnerhochschulen beteiligen.

Insgesamt hat die Helmholtz-Gemeinschaft 14 Nachwuchswissenschaftlerinnen und -wissenschaftler aus 244 Bewerbern ausgewählt, die nun an Zentren der Helmholtz-Gemeinschaft eine eigene Arbeitsgruppe aufbauen können. Drei der Nachwuchsforscher werden diesen wichtigen Karriereschritt am HZI vollziehen. Dort können sie von der Ausstattung des HZI und der Vernetzung mit anderen Infektionsforschern profitieren. Ein weiterer Anreiz dieses Angebots ist, dass die jungen Wissenschaftler ihren eigenen Ideen nachgehen und selbständig forschen können. Die Förderung ermöglicht ihnen über die eigene Stelle hinaus auch die Finanzierung einer eigenen Arbeitsgruppe. Eine nach rund vier Jahren stattfindende Evaluierung entscheidet darüber, ob sich an die Förderperiode eine unbefristete Stelle anschließt. Neben ihrer Forschung werden die drei Wissenschaftler Seminare und Vorlesungen an der Technischen Universität Braunschweig, der Medizinischen Hochschule Hannover beziehungsweise der Universität Saarbrücken halten.

 

Was macht Salmonellen zu potentiell krankmachenden Erregern? Dieser Frage wird Marc Erhardt auf molekularer Ebene nachgehen. Bakterien wie Salmonellen verfügen über ein ausgeklügeltes Transportsystem, das wie eine Spritze funktioniert, die schädliche Moleküle in Wirtszellen injiziert. Erhardt wird am HZI die genaue Zusammensetzung der molekularen Spritzen erforschen. 

Till Strowig interessiert sich dafür, wie das Immunsystem schädliche Erreger und die damit verbundenen Gefahren erkennt. Wie interagieren körpereigene Bakterien, Krankheitserreger und ein spezielles Überwachungssystem des angeborenenen Immunsystems, das „Inflammasom“, miteinander? Welchen Einfluss haben diese Wechselwirkungen darauf, wie das Immunsystem mit Infektionen und Impfungen umgeht? Diese Fragen stehen im Mittelpunkt von Strowigs Forschung.

 

Die Bekämpfung des Krankhauskeims Pseudomonas aeruginosa ist der Forschungsschwerpunkt von Alexander Titz. Diese Bakterien schützen sich vor Antibiotika durch einen schleimigen Biofilm. Diese Schutzschicht möchte Titz verhindern und zerstören, so dass sich die Bakterien nicht weiter verbreiten können. 

 

 

Die drei Wissenschaftler werden ihre Forschung am HZI in Braunschweig und an der Außenstelle in Saarbrücken, dem Helmholtz-Institut für Pharmazeutische Forschung, HIPS, Anfang 2013 aufnehmen.

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