Helicobacter pylori binds human Annexins via Lipopolysaccharide to interfere with Toll-like Receptor 4 signaling

Abstract

Helicobacter pyloricolonizes half of the global population and causes gastritis, peptic ulcer disease or gastric cancer. In this study, we were interested in human annexin (ANX), which comprises a protein family with diverse and partly unknown physiological functions, but with a potential role in microbial infections and possible involvement in gastric cancer. We demonstrate here for the first time thatH.pyloriis able to specifically bind ANXs. Binding studies with purifiedH.pyloriLPS and specificH.pyloriLPS mutant strains indicated binding of ANXA5 to lipid A, which was dependent on the lipid A phosphorylation status. Remarkably, ANXA5 binding almost completely inhibited LPS-mediated Toll-like receptor 4- (TLR4) signaling in a TLR4-specific reporter cell line. Furthermore, the interaction is relevant for gastric colonization, as a mouse-adaptedH.pyloriincreased its ANXA5 binding capacity after gastric passage and its ANXA5 incubationin vitrointerfered with TLR4 signaling. Moreover, both ANXA2 and ANXA5 levels were upregulated inH.pylori-infected human gastric tissue, andH.pylorican be found in close association with ANXs in the human stomach. Furthermore, an inhibitory effect of ANXA5 binding for CagA translocation could be confirmed. Taken together, our results highlight an adaptive ability ofH.pylorito interact with the host cell factor ANX potentially dampening innate immune recognition.