An anti-inflammatory protein of H. pylori: mechanism and diagnostic potential

University Of California Santa Cruz, Santa Cruz CA

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Abstract

DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of how Helicobacter pylori controls host inflammation and, concomitantly, which H. pylori gene products we should screen to predict a strain's disease potential. Continued existence of this gap prevents us from designing diagnostic tools that would allow us to predict which H. pylori infections will progress to disease, and therefore, should be high priorities to cure. Millions of people worldwide and in the U.S. are infected by H. pylori and suffer from its associated diseases-ulcers and gastric cancer. Gastric cancer is the second cause of cancer deaths worldwide. In the U.S., fewer people have gastric cancer likely due to lower but stabilized H. pylori incidence, underlying the idea that curing H. pylori would probably lower the number of cancer deaths. H. pylori infection progresses to disease in only a subset of infected individuals. A key variable is a strain's ability to drive inflammation. The long-term goal of our research is create accurate diagnostics that identify which H. pylori strains will cause trouble. H. pylori strains are highly variable, and this feature offers a possible entr¿e to--and basis for--diagnosti tests. Our recent work has identified a novel anti-inflammatory H. pylori virulence factor, which we named immunomodulatory autotransporter A (ImaA). Our preliminary data show that H. pylori that lack imaA trigger mammalian cells to produce large amounts of inflammation-associated mRNA and protein. ImaA acts through the known H. pylori proinflammatory apparatus, the cag PAI, and is required for sustained phosphorylation of the proinflammatory protein CagA. The specific objective of this work is to determine the molecular basis for ImaA's effect on inflammation, its contribution to H. pylori disease, and whether it serves as a biomarker for severe H. pylori human infections. Our central hypothesis is that ImaA acts to manipulate host phosphorylation of the proinflammatory protein CagA, and that loss of imaA creates H. pylori that cause especially severe disease in gerbils and humans. In the first Aim, we will determine the molecular mechanism by which H. pylori ImaA diminishes cag PAI-dependent pro-inflammatory gene expression. In the second Aim, we will probe how the anti-inflammatory protein ImaA impacts illness by analyzing how loss of imaA affects disease in a relevant animal model and by testing whether the presence of imaA correlates with inflammation and disease outcome in a panel of H. pylori human clinical strains. The proposed research is significant because it will give us a better understanding of the proteins used by H. pylori to control inflammation, and give us another tool with which to probe a particular H. pylori strain's disease potential. The proposed research is innovative in the hypothesis to be tested: that H. pylori produces anti-inflammatory as well as pro-inflammatory proteins. Ultimately the proposed work will inform us about how a new type of virulence factor functions, as well as how it will serve as a disease biomarker and advance our ability to prevent ulcers and gastric cancer.