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).