Malicious at the turn of a button

"Molecular Switch“ turns food bacteria into dangerous germ

08.03.2005

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 (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