Amebic colitis is the most common form of amebiasis, a parasitic disease that accounts for 100,000 annual deaths. Human and experimental data have not clearly documented the nature of protective or deleterious acquired immunity in this infection. Recent work of ours using a C3H mouse model of amebic colitis has documented the capacity for acquired immunity to protect against colonization through vaccination as well as a deleterious role for CD4+ T cells in the development of disease. This research plan aims to focus on the latter, to define the mechanism of the CD4+ T cell response in disease pathogenesis. I hypothesize that dysregulated CD4+ T cells in amebic colitis contribute independently to both parasite burden and the development of intestinal inflammation. Possible mechanisms include IL-4 mediated phagocyte inhibition, mast cell induction, or loss of regulatory TGF-b production. Techniques will include in vivo blockade of key T helper cytokines by monoclonal antibody and depletion of phagocytes and mast cells. Development of the C3H SCID mouse model of infection will allow adoptive transfer experiments using CD4+ T cells and subsets therein to test the role of suppressor versus effector CD4+ T cells on the development of colitis. The work thus bridges the fields of parasite biology and mucosal immunology. Rigorous formal training in parasitology and immunology will occur during the first 2 years of the proposed research plan. The sponsor and cosponsor, investigators in molecular parasitology and mucosal immunology, respectively, will guide the laboratory component of the proposal. Additionally a supportive network of collaborators and consultants will be utilized from the departments of Immunology, Gastroenterology, Infectious Disease and Pathology throughout the University of Virginia and the United States Department of Agriculture. The comprehensive approach in training and research laid out in this research proposal will guide the applicant towards his goal of being an independent investigator in immunoparasitology.
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