Helicobacter pylori chronically infects the human stomach of half the world and approximately a third of the US population. H. pylori induces inflammation in all hosts and 10-20% of those infected will present with severe disease including peptic ulcers and gastric adenocarcinoma. All H. pylori associated diseases depend on the ability of this organism to establish a persistent infection and induce chronic inflammation. Chronic inflammation in the stomach can lead to additional tissue changes including atrophic gastritis (loss of acid-producing parietal cells), spasmolytic polypeptide-expressing metaplasia (SPEM), intestinal metaplasia (IM) and dysplasia that increase risk for adenocarcinoma. In the prior funding period, we documented genetic adaptation of H. pylori strains to these tissue changes during chronic human infection using a combination of whole genome sequence analysis, extensive phenotyping and molecular variant tracking in clinical and population-based samples. We also showed that H. pylori actively modulates the immune microenvironment through collateral delivery of proinflammatory cell envelope associated metabolites during secretion of the toxin CagA via the Cag Type IV Secretion System (T4SS). These data combined with clinical data revealing higher rates of metachronous cancer after early cancer resection in individuals with sustained Hp infection lead us to rethink the model of H. pylori carcinogenesis beyond its role as an initiator of inflammation. We propose that H. pylori promotes carcinogenesis through continual remodeling of the tissue environment to create a favorable niche for long term persistence and transmission. Thus, H. pylori disease is a by-product of the interaction between bacterial factors necessary for establishing and maintaining infection for transmission and resultant host defenses. In our renewal we propose to leverage these culture collections and newly developed mouse models to elucidate the genetic mechanisms that drive these adaptations and the resultant phenotypic changes that accompany metaplastic progression.
Our specific aims are to 1) Identify adaptive genetic variation during chronic infection and preneoplastic tissue changes, 2) Examine phenotypic changes during chronic infection and adaptation to distinct niches and 3) Evaluate the interplay between the epithelial and myeloid compartment in Cag T4SS dependent innate immune activation, bacterial control, and tissue remodeling. Our study of the genes and mechanisms contributing to chronic colonization will identify the mediators of H. pylori persistent infection. Our studies of genetic variation during stomach infection will show how these mediators adapt during the chronic inflammation that leads to severe disease (cancer).
Helicobacter pylori infect the human stomach of 50% of the world?s population where it can cause mild inflammation, ulcer disease and even gastric cancer, depending in part on the genetic diversity of the infecting strain. In this project we study the genes and mechanisms contributing to chronic colonization to identify the mediators of persistent infection. Our studies of genetic variation during stomach infection will show how these mediators adapt during the chronic inflammation that leads to severe disease (cancer).
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