Helicobacter pylori remains the most prevalent infectious disease in the world, with up to100% of people colonized in some populations. Disease due to H. pylori is variable, however: only a minority of infected individuals develops clinical disease. It has become increasingly clear that this variability is attributable to differences in host immune response, and that understanding the immune mechanisms that contribute to disease will be essential for controlling gastritis and the subsequent sequelae such as peptic ulcer disease and cancer. Our laboratory uses an established adoptive transfer model to study the adaptive immune response to H. pylori. CD4 (helper) T cells are necessary and sufficient to induce disease in H. pylori infected mice, and regulatory T cells suppress gastritis. Infection is associated with IFN_ but recent data indicate that, contrary to previous assumptions, several immune pathways including Th1, Th17, and possibly others contribute to gastritis due to H. pylori. Our central hypothesis is that the balance between Th-1, Th-17, and T regulatory cells determines the outcome of gastritis due to H. pylori. Our overall goals are to determine the role of cross-regulation between Th-1 and Th-17 in regulation of gastritis and to determine the mechanism of Treg cells in suppression of Th-1 independent and Th-17 independent gastritis. The two specific aims are:
Aim 1 : To determine the interactions between IFN_ and IL-17 in H. pylori gastritis.
Aim 2 : To determine the mechanism by which CD4CD25Foxp3+ regulatory T cells regulate Th1- or Th17- independent inflammation due to H. pylori. In this revision we have eliminated long-term experiments and thereby decreased the number of mice to be used. This will allow us to hire additional staff to ensure rapid completion of the remaining experiments. With these changes we fully expect to complete these experiments in 2 years.

Public Health Relevance

Infection by Helicobacter pylori is common, but most infected individuals do not develop disease. The goal of this study is to understand how H. pylori interacts with the immune system to create disease in a susceptible host. Identification of the factors that lead to disease will allow identification of those infected individuals who are at risk for disease development, and will identify possible targets for therapy in those who are resistant to currently available treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI043643-08A2
Application #
7730235
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Mills, Melody
Project Start
1998-05-01
Project End
2011-06-30
Budget Start
2009-07-18
Budget End
2010-06-30
Support Year
8
Fiscal Year
2009
Total Cost
$359,513
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

Showing the most recent 10 out of 14 publications