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

Barbara Schmidinger, Kristina Petri, Clara Lettl, Hong Li, Sukumar Namineni, Hellen Ishikawa-Ankerhold, Luisa Fernanda Jiménez-Soto and Rainer Haas

PLOS Pathogens, 2022, vol. 18, issue 2, 1-29

Abstract: Helicobacter pylori colonizes 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 that H. pylori is able to specifically bind ANXs. Binding studies with purified H. pylori LPS and specific H. pylori LPS 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-adapted H. pylori increased its ANXA5 binding capacity after gastric passage and its ANXA5 incubation in vitro interfered with TLR4 signaling. Moreover, both ANXA2 and ANXA5 levels were upregulated in H. pylori-infected human gastric tissue, and H. pylori can 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 of H. pylori to interact with the host cell factor ANX potentially dampening innate immune recognition.Author summary: H. pylori is very well adapted to its natural habitat, the human gastric mucosa. For this purpose, the bacterium has evolved a number of highly specific virulence factors, such as the cag-type IV secretion system, vacuolating cytotoxin A (VacA) or secreted gamma-glutamyl transpeptidase. An important function of these bacterial factors is to manipulate the host immune response to enable a chronic H. pylori infection. The present work identifies a new player in this process. Here, we have discovered that H. pylori, as well as several other bacterial species, can bind human annexins (ANX), suggesting a more widespread phenomenon. We show that H. pylori specifically binds ANXA5 via lipid A. The interaction is strictly dependent on calcium and modulated by the phosphorylation status of lipid A. Notably, ANXA5 binding strongly inhibits LPS-mediated Toll-like receptor 4 (TLR4) signal transduction, suggesting that H. pylori exploits ANXs binding to avoid its recognition by this important receptor of the innate immune system. The study thus provides novel molecular and mechanistic insights into a further strategy of H. pylori to successfully evade recognition by the host.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:plo:ppat00:1010326

DOI: 10.1371/journal.ppat.1010326

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