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To most people, bacteria are pathogens that cause complicated infections. In fact, though, the majority of bacteria are harmless and many are quite useful, especially in the process of digestion. In the times of Robert Koch, they were seen as being equal to cholera, plague and tuberculosis. But hazardous pathogens are the exception rather than the rule and they use clever tricks to seize human cells.

Cleverly infected – The tricks of bacteria

Enteropathogenic Escherichia cobli (EPEC) bacteria inducing a human intestinal cell to produce pedestals. © HZI / Rohde

Evolution has provided the human body with a sophisticated immune system that recognises invaders immediately, eliminates them and recognises them again later on. This is to protect the body from infections - at least in theory. Usually, this works fairly well, but pathogenic bacteria often manage to find a loophole. The ability to proliferate rapidly is their major strength. Under optimal conditions, some species produce a new generation every 15 minutes and each of the new generations is adapted to the host a little better than the previous one. The caries pathogen, Streptococcus mutans, has taken this to the extreme in that it kills other bacteria in the tooth pocket to be able to take up their genetic material in order to obtain new strategies for adaptation. By this means, bacteria have developed a surprising repertoire of tricks over millions of years that allow them to be one step ahead of the human immune system time and again.

Salmonellae, which usually cause diarrhoea in humans, are one prominent example. They often enter the body via food items, like eggs, meat or soft ice cream, and usually end up in the intestines. This is where they stick to the epithelial cells and produce tiny molecular syringes. They use this so-called type 3 secretion system to inject various substances into the intestinal cells and to initiate a surprising mechanism: Using signaling substances, they make intestinal cells evaginate membranes as envelopes for the bacteria. The manipulated cell ultimately takes the Salmonella bacteria up, i.e. the host basically asks the enemy in. The Salmonella bacteria can then proliferate with impunity in the intestinal cells. If they are subjected to some stress by an antibiotic, Salmonella bacteria can reduce their cell division and enter into a kind of resting state. Since many antibiotics kill only actively dividing bacteria, this strategy allows the Salmonella bacteria to survive the attack as sleeper cells or persisters as they are called by experts.

Similar tricks have been detected in pathogenic strains of the intestinal bacterium Escherichia coli: "They induce their host cells to produce evaginations on the surface," says Manfred Rohde, who directs the Central Microscopy Unit at the Helmholtz Centre for Infection Research (HZI). "The misled cell then uses these structures called pedestals to contact the bacteria - this is the first step of infection."

Salmonella bacteria use syringe-like secretion systems (left) to inject toxins and signaling substances, for example into intestinal cells and to make them evaginate membranes (right). © HZI / Rohde

In order to get comfortable in the intestines, E. coli possesses small pumps in its membranes that transport toxic substances, such as the bile salts of the intestine, out of the bacterial cell. Since the efflux pumps can also remove antibiotics, some infections by pathogenic E. coli strains are difficult to treat. And they also are capable of surviving as so-called persisters.

Bacteria from the Yersinia genus are also resourceful pathogens aiming for the human intestines. They use RNA molecules, i.e. copies of the genetic information, to measure the ambient temperature and to find out whether they are outside or inside the host. "At 37°C, the RNA thermometers unfold and make their information accessible," says Petra Dersch, who is the head of the "Molecular Infection Biology" department at the HZI. "This tells the Yersinia cells that they are inside the host and, if they meet defence cells, they multiply their virulence plasmids. These special DNA molecules bear the genetic information that makes the bacteria pathogenic." Yersinia uses this to switch into attack mode and then injects toxic substances into the intestinal cells. In an effort to survive their host cells, Yersinia dissolve their colonies. They then hide, for example, in the appendix as individual cells and shut-down the production of a toxin called CNFY. This makes them invisible to the immune system.

Streptococcus pyogenes with a capsule (yellow) made of sugar molecules, here shown in the blood. © HZI / Rohde

The scarlet fever pathogen Streptococcus pyogenes, which often elicits inflammations of the throat and skin as well, has a direct effect on the human immune response: Infected host cells release a messenger substance called Interleukin-8 and use it to attract defence cells to fight the bacteria. But the streptococci possess the SpyCEP enzyme, which cleaves Interleukin-8 and silences the call for help of their host cells. This is not the only protective mechanism used by streptococci: "Like the hospital pathogen Staphylococcus aureus, streptococci can encapsulate themselves in a thick shell of sugar molecules and prevent defence cells from disintegrating them," says Manfred Rohde.

Any infection, in which the pathogens agglomerate into a biofilm, is particularly difficult to subject to treatment. To this end, the pathogens cross-link sugar molecules outside the cells to produce a matrix, in which they then form a dense colony. This protects the bacteria from attacks of the immune system and allows them to withstand the effect of antibiotics for long periods of time.

Like streptococci, the hospital pathogen Pseudomonas aeruginosa is feared mainly because of this property. It can infect all organs of the body - and even implants - and can cause recurrent pneumonia, sepsis or chronic wound infections. In addition, Pseudomonas bacteria possess efflux pumps that allow them to pump antibiotics out of the bacterial cells. These mechanisms have led to many types of antibiotic resistance by now. For this reason, HZI scientists are searching for alternative agents that weaken bacteria without killing them, giving them no reason for the development of resistance. This anti-virulence strategy is aimed, for example, at signaling pathways or molecules the bacteria use to induce the production of a biofilm. Other approaches aim to inhibit molecular syringes, adhesion proteins or the flagella that is used for motion by some bacterial species. "This type of agent would weaken the pathogens sufficiently such that the immune system - maybe in combination with a low-dose antibiotic - can eliminate them," Petra Dersch says.

Author: Andreas Fischer

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Cover page of HZI staff magazine "InFact", issue 01/2018 © HZI

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