H. pylori has been called the most common infectious disease of humans in the world today. Worldwide, between 50-100% of people are infected with H. pylori, but only a minority of those develop clinical signs of disease. Almost 2 decades of research have resulted in a general consensus that both host and bacterial factors contribute to disease, but the specific bacterial factors involved and the mechanisms whereby they promote colonization and induce severe manifestations of disease are not well understood. The overall goal of this project is to investigate these mechanisms. In the first funding interval we developed a mouse model of severe disease in which the contributions of host and bacterial factors to severe manifestations of disease can be evaluated. We utilized this model to determine the T cell subsets and cytokines that contribute to disease, we identified one bacterial factor, lipopolysaccharide O-antigen, that induces a deleterious host response and thus contributes to the outcome of disease, and we identified an H. pylori promoter, cagl5, that is upregulated in vivo and likely represents a new virulence factor. In this renewal, we will investigate the roles of O-antigen and cagl 5 in H. pylori pathogenesis, and use a newly-developed promoter trap to identify H. pylori genes that are upregulated in vivo. The 3 specific aims are:
Specific aim 1 : To test the hypothesis that cag15 has a role in survival of H. pylori in vivo, and to determine the role of the cagl5 gene product in colonization and disease.
Specific aim 2 : To use a ureB reporter construct for promoter trapping, to identify novel colonization factors that are induced by growth in vivo, and to test the hypothesis that upregulated genes are essential for or facilitate colonization by and/or gastritis due to H. pylori.
Specific aim 3 : To test the hypothesis that the polysaccharide moiety of H. pylori lipopolysaccharide induces gastritis by receptor-mediated activation of antigen presenting cells. Successful completion of these aims will lead to improved understanding of the pathogenesis of H. pylori associated disease and provide a foundation for development of novel therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043643-06
Application #
7066068
Study Section
Special Emphasis Panel (ZRG1-BM-1 (01))
Program Officer
Mills, Melody
Project Start
1998-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
6
Fiscal Year
2006
Total Cost
$272,509
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gray, Brian M; Fontaine, Clinton A; Poe, Sara A et al. (2013) Complex T cell interactions contribute to Helicobacter pylori gastritis in mice. Infect Immun 81:740-52
Eaton, K A; Opp, J S; Gray, B M et al. (2011) Ulcerative typhlocolitis associated with Helicobacter mastomyrinus in telomerase-deficient mice. Vet Pathol 48:713-25
Eaton, Kathryn A; Danon, Stephen J; Krakowka, Steven et al. (2007) A reproducible scoring system for quantification of histologic lesions of inflammatory disease in mouse gastric epithelium. Comp Med 57:57-65
Eaton, Kathryn A; Benson, Lucy H; Haeger, Jennifer et al. (2006) Role of transcription factor T-bet expression by CD4+ cells in gastritis due to Helicobacter pylori in mice. Infect Immun 74:4673-84
Eaton, K A; Logan, S M; Baker, P E et al. (2004) Helicobacter pylori with a truncated lipopolysaccharide O chain fails to induce gastritis in SCID mice injected with splenocytes from wild-type C57BL/6J mice. Infect Immun 72:3925-31
Dailidiene, Daiva; Dailide, Giedrius; Ogura, Keiji et al. (2004) Helicobacter acinonychis: genetic and rodent infection studies of a Helicobacter pylori-like gastric pathogen of cheetahs and other big cats. J Bacteriol 186:356-65
Peterson 2nd, Richard A; Hoepf, Toni; Eaton, Kathryn A (2003) Adoptive transfer of splenocytes in SCID mice implicates CD4+ T cells in apoptosis and epithelial proliferation associated with Helicobacter pylori-induced gastritis. Comp Med 53:498-509
Eaton, Kathryn A; Gilbert, Joanne V; Joyce, Elizabeth A et al. (2002) In vivo complementation of ureB restores the ability of Helicobacter pylori to colonize. Infect Immun 70:771-8
Joyce, E A; Gilbert, J V; Eaton, K A et al. (2001) Differential gene expression from two transcriptional units in the cag pathogenicity island of Helicobacter pylori. Infect Immun 69:4202-9
Eaton, K A; Mefford, M; Thevenot, T (2001) The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice. J Immunol 166:7456-61

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