Helicobacter pylori chronically infect 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 cancers. All H. pylori associated diseases depend on the ability of this organism to establish a persistent infection and induce chronic inflammation. Thus H. pylori disease is a by-product of the interaction between bacterial factors necessary for establishing and maintaining infection and the resultant host defenses. This interaction is dynamic with both the bacteria and host changing over decades of infection. To study this complex process, we utilize a mouse model of infection and we study genetic variation among isolates from human clinical populations. Work in previous funding periods established tools and methods necessary to take a functional genomic approach to define molecular mechanisms of pathogenesis for this organism, which is evolutionary distant from better studied enteric pathogens, including whole genome sequencing, in vivo colonization screens, and both random and an ordered sequence defined mutant libraries. Convergence of our genetic and population-based studies drives the focus of our proposed studies on DNA repair, uptake and genetic diversification as well as cell envelope proteins that appear to influence host responses. This will be accomplished in three Aims that: 1. Evaluate DNA repair as a target for H. pylori eradication therapy, 2. Explore the mechanisms and consequences of genetic variation during transmission and chronic infection, both in humans and a mouse stomach colonization model, and 3. Perform functional analysis of bacterial factors that promote and inhibit infection. Our study of the genes contributing to virulence will identify the mediators of persistent infection and studies of genetic variation in te clinical population will show how these mediators adapt during the chronic inflammation that is associated with infection and leads to severe disease (ulcer, cancer). Our study of the mechanisms by which H. pylori promotes genetic exchange and diversification should also increase understanding of the spread of antimicrobial resistance, an increasing clinical problem in the treatment of H. pylori, thus advancing the mission of NIAID to understand and treat infectious diseases.

Public Health Relevance

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 ask whether the proteins required for DNA repair and genetic diversification could be exploited as a target for antimicrobial therapy and consequences of genetic diversification for transmission and chronic infection. Our work will identify targets for develoinvestigatorng antimicrobial therainvestigatore and bring new knowledge on the molecular mechanisms of pathogenesis and the development and spread of antimicrobial resistance.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mills, Melody
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Fred Hutchinson Cancer Research Center
United States
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Keilberg, Daniela; Zavros, Yana; Shepherd, Benjamin et al. (2016) Spatial and Temporal Shifts in Bacterial Biogeography and Gland Occupation during the Development of a Chronic Infection. MBio 7:
Talarico, Sarah; Safaeian, Mahboobeh; Gonzalez, Paula et al. (2016) Quantitative Detection and Genotyping of Helicobacter pylori from Stool using Droplet Digital PCR Reveals Variation in Bacterial Loads that Correlates with cagA Virulence Gene Carriage. Helicobacter 21:325-33
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Sycuro, Laura K; Wyckoff, Timna J; Biboy, Jacob et al. (2012) Multiple peptidoglycan modification networks modulate Helicobacter pylori's cell shape, motility, and colonization potential. PLoS Pathog 8:e1002603
Talarico, Sarah; Whitefield, Shawn E; Fero, Jutta et al. (2012) Regulation of Helicobacter pylori adherence by gene conversion. Mol Microbiol 84:1050-61
Dorer, Marion S; Sessler, Tate H; Salama, Nina R (2011) Recombination and DNA repair in Helicobacter pylori. Annu Rev Microbiol 65:329-48

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