Helicobacter pylori downregulates expression of human β-defensin 1 in the gastric mucosa in a type IV secretion-dependent fashion

Helicobacter pylori establishes a chronic lifelong infection in the human gastric mucosa, which may lead to peptic ulcer disease or gastric adenocarcinoma. The human beta-defensins (hDs) are antimicrobial peptides, hD1 being constitutively expressed in the human stomach. We hypothesized that H.pylori may persist, in part, by downregulating gastric hD1 expression. We measured hD1 and hD2 expression in vivo in relation to the presence, density and severity of H.pylori infection, investigated differential effects of H.pylori virulence factors, and studied underlying signalling mechanisms in vitro. Significantly lower hD1 and higher hD2 mRNA and protein concentrations were present in gastric biopsies from infected patients. Those patients with higher-level bacterial colonization and inflammation had significantly lower hD1 expression, but there were no differences in hD2. H.pylori infection of human gastric epithelial cell lines also downregulated hD1. Using wild-type strains and isogenic mutants, we showed that a functionalcag pathogenicity island-encoded type IV secretion system induced this downregulation. Treatment with chemical inhibitors or siRNA revealed that H.pylori usurped NF-B signalling to modulate hD1 expression. These data indicate that H.pylori downregulates hD1 expression via NF-B signalling, and suggest that this may promote bacterial survival and persistence in the gastric niche.