Medical research

Bacterial Toxin Facilitates Infection

4.12.2013 | More than five million people die of gastro-intestinal diseases each year. Researchers from Braunschweig, Germany, have now discovered a molecule in a typical bacterial strain that facilitates the infection process considerably. The bacteria are transmitted via contaminated food.
The bacterial strain Yersinia pseudotuberculosis is one of the main causes for serious gastro-intestinal diseases. Some of these bacteria produce a molecule called CNFy: it changes the host cells in a way that the "injection apparatus" of Yersinia, which injects toxins into the cells, can work more efficiently. This in turn strengthens the infection and leads to further tissue inflammation.

Whether an immune cell divides, alarms other immune cells or dies, is controlled by our immune system. "Molecular switches" influence these processes and basically set the course for different pathways. In light of the evolutionary competition between the immune system and microbes, researchers have found that bacteria produce different substances to manipulate these "switches" to their advantage.

Yersinia (blue) cause serious infections
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Yersinia (blue) cause serious infections
Scientists at the Helmholtz Centre for Infection Research HZI in Braunschweig, and at the Hannover Medical School MHH, have examined one of those substances in detail. The team led by Prof. Petra Dersch, head of the department "Molecular Infection Biology", took notice of the molecule CNFy because Yersinia pseudotuberculosis produce it in large quantities. However, not all strains produce CNFy. The scientists had therefore assumed that it didn't play a significant role. The interdisciplinary team has now shown that this was a misjudgement. "Bacteria only produce molecules that are useful for their purposes. Therefore, we wanted to know why Yersinia would need CNFy", Dersch explains.

In order to elucidate its function, the scientists genetically modified a bacterial strain that usually produces CNFy into a strain without this capability. "The altered bacterium was no longer capable of escaping the immune system of the host organism and could not cause disease", reports Janina Schweer, a PhD student at the HZI. This is remarkable since the bacteria certainly have other pathogenic characteristics in their repertoire: they have large molecular complexes at their disposal to inject destructive substances into the host cell. This is actually a very effective method to promote infection.

"It seems that this mechanism is not sufficiently active in some Yersinia. Apparently, the examined Yersinia strain needs CNFy so that its 'molecular syringes' can inject sufficient quantities of active substances into the immune cells", explains Prof. Jochen Hühn, head of the department "Experimental Immunology" at the HZI. These active substances, mostly cell toxins, damage the immune cells. Many of the substances cause cell mortality. This facilitates the expansion of Yersinia within the infected organism. During advanced infections, inflammation occurs as well as tissue damage.

The researchers have also identified the molecular target that CNFy manipulates: this involves the so-called small Rho GTPases. These enzymes initiate a whole cascade of events, for example alterations of the cytoskeleton. This bring about pores in the host cell surface through which bacterial syringes can more efficiently transport active agents into the cell. The observed cell mortality of the immune cells is introduced through Rho GTPases as well. "We have discovered a very clever strategy of Yersinia pseudotuberculosis. With the aid of CNFy, the bacterium manipulates the host cell in such a manner that the injection apparatus can work more effectively", explains Dersch. "It sets the course for an efficient infection and triggers the onset of the disease."

The present study shows that CNFy is very important for Yersinia. At the same time, it emphasises the central role of the injection apparatus that is deployed in a more robust manner via CNFy – this is, and remains, an important drug target for future intervention measures.   (© Helmholtz-Zentrum für Infektionsforschung)
Dr. Birgit Manno

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Source

  • Janina Schweer, Devesha Kulkarni, Annika Kochut, Jörn Pezoldt, Fabio Pisano, Marina C. Pils, Harald Genth, Jochen Hühn und Petra Dersch: The cytotoxic necrotizing factor of Yersinia pseudotuberculosis (CNFy) enhances inflammation and Yop delivery during infection by activation of Rho GTPases, PLOS Pathogens, 07.Nov 2013, DOI: 10.1371/journal.ppat.1003746

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