Infection with Helicobacter pylori leads to chronic gastritis in virtually all persons who harbor the organism. Despite host immune recognition of H. pylori, the bacteria persist in the stomach for years unless eradicated by antibiotic therapy. The majority of infections with H. pylori are clinically silent, however in some persons, infection may lead to the development of ulcer disease or gastric carcinoma. The factors that determine the outcome of H. pylori infection, i.e., """"""""benign"""""""" asymptomatic infection, ulcer disease, or cancer, are poorly understood. It is unclear, for example, whether strain differences in expression of virulence factors or detrimental host inflammatory responses are the major contributors to pathology. Current data suggest that both host inflammatory responses and genetic characteristics of the infecting organisms differ in patients with peptic ulcer disease versus those with gastritis alone. Higher gastric mucosal levels of IL-8 are associated with increased inflammation, higher frequency of peptic ulcer disease, and with infection by strains that possess cagA and produce functional vacuolating cytoxin. While strains that have the cagA gene and produce vacuolating cytoxin have increased virulence, 50-60% of H. pylori isolates possess these characteristics, yet only a small minority of individuals infected with such strains develop peptic ulcer disease. These observations suggest that additional virulence factors influence host response and the ultimate outcome of infection. An approach was devised to identify genetic differences between strains that lead to production of additional virulence factors. This strategy led to the identification and cloning of a novel H. pylori gene, iceA. Strains that possess iceA 1 are significantly associated with peptic ulcer disease (p=0.0005) and with higher levels of gastric mucosal IL-8 (p=0.008). These results support the central hypothesis of this application, that host response varies with differences in the infecting H. pylori strain. To investigate the mechanisms by which strain differences influence host response and outcome, this proposal has three specific aims: 1) To investigate the regulation of iceA mRNA expression; 2) To characterize the function of ice A protein in H. pylori; 3) To determine whether iceA 1 interacts with cagA, vacA, or picB in the induction of IL-8 secretion by gastric epithelial cells.
