Helicobacter pylori allelic variation in cell surface genes influences human exoproteome binding and stomach tissue adherence

Helicobacter pylori, the primary etiological agent of gastric cancer, requires chronic infection to promote severe disease. Throughout colonization, the bacteria accumulate genetic variation, which can reshape the interaction between host and pathogen. In this study, we probed adherence as one important characteristic of this relationship. We leveraged a panel of H. pylori strains, representing both inter- and intra-host diversity, and BASEHIT, a comprehensive barcoded yeast display library of the human exoproteome, to evaluate the human exoprotein binding characteristics of H. pylori. We identified a set of lineage-correlated binding phenotypes and a set of polymorphic cell surface-associated loci that we predict to govern heterogeneous binding. We also identified a general increase in gastric tissue adherence during mouse passage and structural modifications in the O-antigen component lipopolysaccharide. Subsequent sequence analyses identified C-terminal repeat length reduction in either futB or glycosyltransferase family 25 galactose transferases as sufficient to alter lipopolysaccharide. Shorter repeat variants were favored during both acute and chronic colonization and conferred a colonization advantage in coinfection. Our data indicate that shorter enzymes, and the resulting shorter O-antigen repeats, are favored during infection. We hypothesize that repeat length polymorphisms modulate enzyme efficiency and disrupt the balance of competing reactions required for O-antigen synthesis. ImportanceIn this study, we used a high throughput assay to evaluate the adherence of genetically diverse Helicobacter pylori isolates to human proteins they may encounter in the stomach. We showed that more closely related H. pylori strains bind human proteins similarly. We linked changes in bacterial binding to genetic differences affecting cell surface components. In particular, H. pylori strains passaged through mice exhibited increased adherence to stomach tissue, which we associated with structural variation in the enzymes responsible for synthesizing the O-antigen portion of lipopolysaccharide. We also showed that shorter enzyme variants produce distinct O-antigen structures that enhance colonization of the mouse stomach.