Helicobacter pylori is a gram-negative, microaerophilic bacterium of the Epsilonproteobacteria and the dominant member of the gastric microbiota that has colonized the stomach mucosa since early in human evolution. H. pylori usually does not cause illness, but colonization with strains bearing the cag (cytotoxin-associated gene) pathogenicity island is associated with increased risk of noncardia gastric adenocarcinoma and peptic ulcer disease.

The most thoroughly studied H. pylori proteins that interact with human cells are CagA and VacA. CagA is an effector protein injected into gastric epithelial cells by a type IV secretion system encoded by the cag pathogenicity island (cagPAI). VacA is initially secreted from the bacterial cell by an autotransporter mechanism. Inside the host cell, phosphorylation of CagA on EPIYA repeats in its phosphotyrosine (PY) region induces cellular elongation known as the hummingbird phenotype. CagA may also induce secretion of IL-8 and disrupt epithelial barrier function, but its immune modulatory effects are incompletely understood.

Phylogenetic analysis of the host-interactive genes vacA and cagA for the seven complete H. pylori genomes shows substantial divergence of Amerindian (V225d and Shi470) from Old World (P12, G27, HPAG1, J99 and 26695) strains with potential immunological relevance.

MIEP will create a computational and mathematical model that mimics H. pylori infection and the immune responses elicited by the bacterium in the gastric mucosa and gastric lymph nodes. MIEP will focus its initial efforts on the European strain 26695, the Sydney Strain 1 (SS1) and the African strain J99. By combining the Center’s experimental approaches and computational capabilities MIEP will improve our understanding of the mechanisms of immune modulation by H. pylori and its role as a commensal versus pathogenic organism.