Helicobacter pylori (Hp) chronically infect the human stomach of 50% of the population worldwide. Ten to 20% of those infected will eventually present with severe disease including ulcers and gastric cancers. Our working hypothesis is that Hp disease is a by-product of the interaction between bacterial factors necessary for establishing and maintaining infection and the resultant host defenses. Furthermore, this interaction is dynamic with the bacteria modifying the host and the host modifying the bacteria over decades of infection. To study this complex process, we utilize a mouse model of infection which recapitulates many aspects of human disease including a robust immune response that is unable to clear the infection and alteration of gastric gland architecture. Using this model we will characterize the function of known Hp virulence factors in vivo and perform a saturating screen for new Hp virulence genes. Such a screen has not been possible until recently due to lack of experimental tools.
In Aim 1 we examine the in vivo role of the major secreted cytotoxin, VacA, which we were the first to demonstrate has a phenotype during mouse infection.
In Aim 2 we describe a screen to identify additional Hp virulence genes. Here we take advantage of two tools we recently developed: an Hp transposon mutant library and a novel methodology we call MATT to monitor transposon mutants in a pool using our Hp cDNA microarray. We believe this screen has the potential to gives us a global view of the Hp genetic requirements for establishing and maintaining infection. Finally, in Aim 3 we investigate the PAI, a group of virulence genes that have been recently shown to mediate a number of specific interactions with cultured cells. We describe experiments that address why no in vivo phenotype for this locus has been described to date and new experiments to measure a role for the PAI during mouse infection. Careful study of infection with mutants in vacA, the PAI genes and newly identified virulence factors have the potential to teach us a great deal about wild type infection by revealing process that fail to occur in mutant infections. These processes likely contribute to the various diseases associated with Hp and may highlight potential therapeutic targets. ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BM-1 (01))
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Van de Verg, Lillian L
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Fred Hutchinson Cancer Research Center
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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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