In its most extreme manifestations H. pylori can be responsible for severe and even life-threatening disease ranging from peptic ulcer to gastric cancer. In spite of the frequent occurrence of infection by H. pylori, however (up to 100 percent in some populations), severe manifestations of disease are relatively rare. Only a minority of infected individuals develop severe or clinically significant disease. The factors which determine disease severity in an individual host are not known. Understanding of these factors is vital to the effective control of H. pylori associated disease, however. Because infection is so common, eradication is not practical, and because most infections are subclinical, severe manifestations of disease cannot be predicted or prevented. Thus, treatment and prevention of disease associated with H. pylori necessitate understanding of the factors that determine disease severity. The goal of this proposal is to identify host and bacterial factors which predispose infected individuals to severe manifestations of disease. The central hypothesis is that gastric disease associated with H. pylori is due to uncontrolled or dysregulated mucosal immune responses to specific bacterial antigens. These host responses result in inflammation and subsequent tissue damage and are responsible for the clinical manifestations of infection by H. pylori. Thus, the two main hypotheses to be addressed are: 1) that severe manifestations of disease are due to dysregulated host immunity; and 2) that specific bacterial virulence factors induce the pathogenic immune response. We will test these hypotheses by 1) identifying the immune cell subsets and cytokines involved in gastritis (via adoptive transfer of lymphocytes, in situ identification of cells and cytokines, and evaluation of the dependence of gastritis on T cells and cytokines in immunologic mouse mutants), 2) determining the role of specific bacterial proteins (cag-related proteins and others) in induction of the pathogenic host response, and 3) determining if loss of expression of these proteins (by insertional or deletional mutagenesis) is associated with diminished ability of H. pylori to induce severe disease in a susceptible host.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI043643-01
Application #
2689786
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O2))
Program Officer
Melnick Seitz, Sandra
Project Start
1998-05-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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

Showing the most recent 10 out of 14 publications