Many Gram-negative pathogens harbor type IV secretion systems (T4SSs) that translocate bacterial virulence factors into host cells to hijack cellular processes for multiple purposes. _Helicobacter pylori_ is a human-specific bacterium that causes persistent infections in the stomach associated with pathologies ranging from chronic gastritis, peptic ulceration to gastric cancer. The virulence of _H. pylori _strongly depends on the serine protease HtrA, the T4SS encoded by the cytotoxin-associated genes_ _(_cag_) pathogenicity island and the injected effector protein CagA. This T4SS forms a needle-like pilus, which is induced upon host cell contact, and its assembly is accomplished by multiple protein-protein interactions. We discovered two gastric cancer-associated single nucleotide polymorphisms (SNPs) in the bacteria, which control effective T4SS functions upon infection of polarized gastric epithelial cells. Those include an alanine-to-threonine polymorphism in the tyrosine phosphorylation motif EPIYA-B of CagA, which affects gastric cancer risk by modifying intracellular signal transduction events involved in inflammation and cell division. The second SNP causes a serine-to-leucine change in HtrA that is associated with (i) elevated trimer formation and proteolytic activity, (ii) boosted cleavage of epithelial junction proteins occludin, claudin-8 and E-cadherin, (iii) induction of paracellular _H. pylori_ transmigration, (iv) pronounced T4SS-pilus formation and injection of CagA, (v) promoted gastric inflammation and β-catenin-mediated cell proliferation as well as (vi) enhanced introduction of DNA double-strand breaks (DSBs) in the host chromosome and micronuclei formation upon infection. These activities highlight the importance of the _cag_ T4SS and SNPs in bacterial virulence, which co-operatively elicit malignant alterations in the gastric epitheliumthat are discussed.

Adelin BARBACCI .