Abstract
ABSTRACTStrains of Helicobacter pylori that cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by the cag pathogenicity island (cagPAI). CagY is an ortholog of VirB10 that, unlike other VirB10 orthologs, has a large middle repeat region (MRR) with extensive repetitive sequence motifs, which undergo CD4+ T cell-dependent recombination during infection of mice. Recombination in the CagY MRR reduces T4SS function, diminishes the host inflammatory response, and enables the bacteria to colonize at a higher density. Since CagY is known to bind human α5β1 integrin, we tested the hypothesis that recombination in the CagY MRR regulates T4SS function by modulating binding to α5β1 integrin. Using a cell-free microfluidic assay, we found that H. pylori binding to α5β1 integrin under shear flow is dependent on the CagY MRR, but independent of the presence of the T4SS pili, which are only formed when H. pylori is in contact with host cells. Similarly, expression of CagY in the absence of other T4SS genes was necessary and sufficient for whole bacterial cell binding to α5β1 integrin. Bacteria with variant cagY alleles that reduced T4SS function showed comparable reduction in binding to α5β1 integrin, although CagY was still expressed on the bacterial surface. We speculate that cagY-dependent modulation of H. pylori T4SS function is mediated by alterations in binding to α5β1 integrin, which in turn regulates the host inflammatory response so as to maximize persistent infection.
Highlights
Strains of Helicobacter pylori that cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by the cag pathogenicity island
To demonstrate binding of intact live H. pylori cells to 1 integrin, we developed a microfluidic assay in which human recombinant ␣51 integrin was coated onto glass coverslips, which served as the substrate of a flow channel (Fig. 1A)
Yersinia InvA was expressed in E. coli after isopropyl -D-1-thiogalactopyranoside (IPTG) stimulation and was presented on the bacterial cell surface (Fig. 1B)
Summary
Strains of Helicobacter pylori that cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by the cag pathogenicity island (cagPAI). We speculate that cagY-dependent modulation of H. pylori T4SS function is mediated by alterations in binding to ␣51 integrin, which in turn regulates the host inflammatory response so as to maximize persistent infection. The major H. pylori virulence factor that determines whether infection causes disease or asymptomatic colonization is the type IV secretion system (T4SS), a sort of molecular syringe that injects bacterial products into gastric epithelial cells and alters host cell physiology. We found that these recombination events produce parallel changes in specific binding to ␣51 integrin, a host cell receptor that is essential for T4SS-dependent translocation of bacterial effectors. H. pylori binding to integrins has only occasionally been performed with intact bacterial cells [12, 18], and the role of the cagPAI-encoded proteins for integrin binding has not yet been examined in the context of a fully assembled T4SS
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