The Role of beta-defensin 2 in the Pathogenesis of Helicobacter pylori

We utilized the rhesus macaque model to interrogate the host gene expression response to infection with Helicobacter pylori. We previously demonstrated that rhesus macaques infected with a cag pathogenicity island (cagPAI) containing strain of H. pylori (WT) mounted a robust innate immune response, including expression of the antimicrobial peptide beta-defensin2 (BD2). Experiments comparing the host response after challenge with WT and isogenic cagPAI knockout H. pylori showed that BD2 induction was cagPAI dependent. Immunohistochemistry showed that BD2 expression at the epithelium was also cagPAI dependent. BD2 expression and WT H. pylori colonization levels were greater in the antrum compared to the corpus of experimentally infected rhesus macaques and were reversed in naturally infected rhesus macaques. Since H. pylori colonization levels were positively associated with BD2 expression and a functional cagPAI was shown to be essential for increased BD2 expression, we hypothesized that increased BD2 expression levels might give WT H. pylori a competitive colonization advantage. While this would be paradoxical, if H. pylori were sensitive to BD2, many clinical H. pylori isolates were relatively resistant to the antimicrobial activity of this peptide. Human BD2 was shown to be gene copy number (GCN) polymorphic, ranging from 2-12 copies. Rhesus macaques encode for up to nine closely related BD2 paralogues, which suggested that rhesus macaque BD2 may be GCN polymorphic. Quantitative RT-PCR-based assays of GCN confirmed that rhesus macaque BD2 was GCN polymorphic. No association between BD2 GCN and H. pylori colonization was found, which suggested that BD2 might not be active in the gastric mucosa. Alternatively, BD2 may be active, but not expressed at sufficient levels to impact H. pylori colonization, or perhaps the presumed GCN-dependent differences in peptide expression levels are modest and might not significantly alter colonization. Finally, to further study host-pathogen interactions we developed a transgenic mouse model that expresses human BD2 in the gastric mucosa. Preliminary experiments suggest that a BD2-sensitive H. pylori strain was capable of colonizing BD2 transgenic mice as well as their wild type litter mates. WT H. pylori induces BD2, which does not decrease bacterial colonization, and might enhance H. pylori fitness.