Helicobacter pylori chronically infect the human stomach of 50% of the population worldwide. Ten to 30% of those infected will present with severe disease including peptic ulcers and gastric cancers15. H. pylori associated diseases cannot be attributed solely to expression of particular bacterial toxins. Instead, our overall working hypothesis is that 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 study genetic variation among isolates from human clinical populations. Our in vivo screen for H. pylori colonization genes in the previous funding period showed 29% of genes tested had a colonization defect and 60% of our colonization genes showed strain specific phenotypes16. This analysis, of over half of the genome, confirmed pathways previously implicated, but also identified unexpected and less well studied classes of genes, including genes involved in DNA uptake and modification plus a large number of hypothetical proteins (81). In our renewal we focus on completing our global analysis of genes contributing to stomach colonization and explore the mechanisms by which genes involved in natural competence for DNA transformation and recombination-based DNA repair promote infection. H. pylori's natural competence allows recombination between super-infecting strains to generate new genotypes during infection and spread of new alleles generated within a strain population. We will explore the roles DNA exchange and recombination-based repair may play during infection of a single strain including 1.) repair of DNA damage encountered during infection 2.) generation of adaptive genetic variation and 3). catalysis of genetic switching events affecting the expression of genes promoting (or limiting) colonization. Our efforts to fully map the genes contributing to virulence will identify the mediators of persistent infection and studies of genetic variation in the clinical population will show how these mediators adapt during 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. This fits the mission of NIAID to understand and treat infectious diseases.
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 which genes are necessary for persistent colonization and test whether the ability to diversify the genome through genetic exchange and recombination with other bacteria is in fact required for successful colonization. Our work will identify targets for developing antimicrobial therapies and, through the study of genetic exchange, bring new knowledge on the mechanisms by which antimicrobial resistance is spread through bacterial populations.
|Blair, Kris M; Mears, Kevin S; Taylor, Jennifer A et al. (2018) The Helicobacter pylori cell shape promoting protein Csd5 interacts with the cell wall, MurF, and the bacterial cytoskeleton. Mol Microbiol 110:114-127|
|Talarico, Sarah; Leverich, Christina K; Wei, Bing et al. (2018) Increased H. pylori stool shedding and EPIYA-D cagA alleles are associated with gastric cancer in an East Asian hospital. PLoS One 13:e0202925|
|Talarico, Sarah; Korson, Andrew S; Leverich, Christina K et al. (2018) High prevalence of Helicobacter pylori clarithromycin resistance mutations among Seattle patients measured by droplet digital PCR. Helicobacter 23:e12472|
|Gall, Alevtina; Gaudet, Ryan G; Gray-Owen, Scott D et al. (2017) TIFA Signaling in Gastric Epithelial Cells Initiates the cag Type 4 Secretion System-Dependent Innate Immune Response to Helicobacter pylori Infection. MBio 8:|
|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|
|Liu, Hui; Fero, Jutta B; Mendez, Melissa et al. (2015) Analysis of a single Helicobacter pylori strain over a 10-year period in a primate model. Int J Med Microbiol 305:392-403|
|Belogolova, Elena; Bauer, Bianca; Pompaiah, Malvika et al. (2013) Helicobacter pylori outer membrane protein HopQ identified as a novel T4SS-associated virulence factor. Cell Microbiol 15:1896-912|
|Dorer, Marion S; Cohen, Ilana E; Sessler, Tate H et al. (2013) Natural competence promotes Helicobacter pylori chronic infection. Infect Immun 81:209-15|
|Salama, Nina R; Hartung, Mara L; Muller, Anne (2013) Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol 11:385-99|
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