Helicobacter pylori infection
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    Instrumental to the persistence of H. pylori in the gastric mucosa is the panel of unique virulence factors that the bacteria use to deregulate the immune system and the cell signalling pathways. Numerous studies have focused on the elucidation of H. pylori pathogenicity mechanisms. The cag-PAthogenicity Island (Cag-PAI), consisting of a group of 27 genes involved in the biogenesis of a type IV secretion system (T4SS) and the translocation of the immunodominant CagA antigen, has been shown to contribute to the induction of the pro-inflammatory IL-8 cytokine by host epithelial cells through the activation of the nuclear factor B (NFB) pathway, and thus has been recognized as one of the major pro-inflammatory players. T4SSs are ubiquitous secretion machineries formed by at least 12 proteins named VirB1-B11 and VirD4, three of them (VirB4, VirB11, and VirD4) are ATPases believed to power the assembly of the T4SS and drive substrates through it. The CagT4SS is distant from the prototypal Agrobacterium T4SS and shows specific features (see Terradot and Waksman, 2011).


    After translocation by the T4SS, CagA is tyrosine phosphorylated by Src kinases and highjacks the signaling system of the cell: phosphorylated CagA binds to Src homology 2 (SH2) domains containing tyrosine phosphatase activity or binds to numerous host molecules involved in a variety of signal transduction pathways. However, independently of phosphorylation, CagA interacts also with other signaling molecules, interactions that trigger morphological changes and disrupt the barrier function of the cell. Altogether, CagA delivery facilitates the colonization of H. pylori and subsequent development of gastric carcinoma. CagA is therefore a major determinant of cancer development during H. pylori infection and is considered the paradigm of “bacterial carcinogenesis”.


    We have solved the crystal structure of a large CagA fragment. The structure revealed a completely new combination of domains (Kaplan-Türköz et al., 2012). Furthermore, by identifying key areas in the structure and using yeast-two hybrid assays, our collaborators (Prof. Rainer Haas, LMU, Munich) demonstrated that a single layer beta sheet in the CagA N-terminal interacts with integrin β1 and that the interaction is necessary for CagA translocation.