Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence

Abstract

SUMMARY The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood-group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive but binding is restored by pH neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions; changes during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA’s extraordinary reversible acid-responsiveness enables tight mucosal bacterial adherence while at the same time allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutations and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, and BabA’s adaptive evolution contributes importantly to H. pylori persistence and to overt gastric disease.

Helicobacter pylori adhesin HopQ disrupts trans dimerization in human CEACAM s

“…Both proteins showed similar binding levels to MKN45 cells, a gastric adenocarcinoma cell line expressing CEACAM1, 5, and 6 (Javaheri et al , ), but did not bind MKN28 cells, which lack surface‐exposed CEACAMs (Fig C). HopQ AD‐I and HopQ AD‐II both retained similar binding levels to MKN45 at pH 7 or pH 2, showing that, unlike the BabA adhesin, HopQ‐binding is resistant to low pH conditions (Fig D; Bugaytsova et al , ).…”

“…Genomic analyses underscore a strong association and co‐evolution with human populations predating ancient migrations (Atherton & Blaser, ). H. pylori 's extensive host adaptation allows it to avoid or temporarily withstand the noxious gastric low pH environment (Moore et al , ; Bugaytsova et al , ) and to evade innate and adaptive immune responses (Salama et al , ), resulting in a lifelong infection of the gastric mucosa. Infection results in usually asymptomatic gastritis, but prolonged exposure to more virulent strains leads to severe clinical symptoms such as gastric and duodenal ulcers, and malignant transformation resulting in gastric lymphomas and adenocarcinomas (Peek & Blaser, ; Polk & Peek, ).…”

Hop‐family Helicobacter outer membrane adhesins form a novel class of Type 5‐like secretion proteins with an interrupted β‐barrel domain

“…The non‐heated sample, however, shifted to an apparent MW of ~150 kDa, suggesting it ran as a folded, oligomeric species. An equivalent non‐covalent oligomer is observed for the high affinity conformation of native BabA isolated from H. pylori outer membranes (Moonens et al ., ; Bugaytsova et al ., ). DDM‐extracted BabA purified from the E. coli OM also shows a nanomolar avidity similar to the native protein (Moonens et al ., ).…”

“…C) depends on the presence of the BabA adhesin domain, and that the BabA oligomer contains individual β‐barrels rather than a single composit TM domain. This is further corroborated by previous observations of a pH‐sensitive monomer‐oligomer equilibrium of native BabA in H. pylori outer membranes (Bugaytsova et al ., ).…”

Pathogenesis of Helicobacter pylori infection

“…It binds to ABO/Le b blood group antigens (Leb) and fucosylated carbohydrates expressed by gastric epithelial cells and mucins. H. pylori BabA‐mediated binding has been recently reported to be acid sensitive, responsive to and reversible by increasing pH . Interestingly, the BabA protein sequence impacts acid sensitivity in Leb binding and plays an essential role in acid adaptation of bacteria in response to variations in acid secretion during disease progression.…”