Helicobacter pylori, the causative agent of type B gastritis, peptic ulcers, gastric adenocarcinoma and MALT lymphoma, uses the Cag type IV secretion system to induce a strong proinflammatory response in the gastric mucosa and to inject its effector protein CagA into gastric cells. CagA translocation results in altered host cell gene expression profiles and cytoskeletal rearrangements, and it is considered as a major bacterial virulence trait. Recently, it has been shown that binding of the type IV secretion apparatus to integrin receptors on target cells is a crucial step in the translocation process. Several bacterial proteins, including the Cag-specific components CagL and CagI, have been involved in this interaction. Here, we have examined the localization and interactions of CagI in the bacterial cell. Since the cagI gene overlaps and is co-transcribed with the cagL gene, the role of CagI for type IV secretion system function has been difficult to assess, and conflicting results have been reported regarding its involvement in the proinflammatory response. Using a marker-free gene deletion approach and genetic complementation, we show now that CagI is an essential component of the Cag type IV secretion apparatus for both CagA translocation and interleukin-8 induction. CagI is distributed over soluble and membrane-associated pools and seems to be partly surface-exposed. Deletion of several genes encoding essential Cag components has an impact on protein levels of CagI and CagL, suggesting that both proteins require partial assembly of the secretion apparatus. Finally, we show by co-immunoprecipitation that CagI and CagL interact with each other. Taken together, our results indicate that CagI and CagL form a functional complex which is formed at a late stage of secretion apparatus assembly.

Background: An Arg-Gly-Asp (RGD) motif in CagL anchors Helicobacter pylori to host cell integrins. Results: Reduced pH causes a conformational change in CagL that buries the RGD motif. Conclusion: A pH-induced conformational change regulates CagL RGD binding to host cells. Significance: Regulation of the RGD-integrin interaction prevents premature host cell attachment.

Infections with the human gastric pathogen Helicobacter pylori are among the most common infections worldwide, causing a significant burden of disease due to their association with gastric carcinogenesis. A hallmark of acute and chronic H. pylori infection is intense inflammation in the gastric submucosa, which is strongly enhanced by the activity of a major bacterial virulence factor, the cytotoxin-associated gene (Cag)-type IV secretion system (T4SS). Despite intense research in recent years, the molecular mechanisms leading to proinflammatory signaling by the Cag-T4SS are only partly understood. Barrozo et al. now show that this proinflammatory capability of H. pylori can be reduced or increased in vivo by recombination events in a particular repeat region of the T4SS component CagY, and that lymphocytes are the main driving force triggering such events. The results highlight the mutual interplay between a major bacterial virulence factor and the immune system and might aid in understanding bacterial persistence.