(Taken from application) Human infection with Leishmania chagasi, the protozoan causing South American visceral leishmaniasis (VL), can lead to either subclinical infection or fatal visceralizing disease. Symptomatic VL causes massive hepatosplenomegaly and suppression of cellular immune responses to parasite antigens. A principal cytokine leading to cure of VL or protective immunity is interferon-gamma (IFN-g). Using a mouse model we found that L. chagasi preferentially replicates in the livers of mice, and that soluble inhibitors of IFN-g production are present locally in liver granulomas, but not in the systemic immune compartment as reflected in splenocyte cultures. The inhibitors, of which one is likely TGF-B, are not functional in immunized mice. At this juncture it is appropriate to determine whether mechanisms suppressing or allowing immune responses in mouse liver granulomas and in human cells are the same.
Specific aims of this project are: (1) To study the mechanisms causing defective proliferation and cytokine production by lymphocytes from Brazilian patients with VL and by granuloma cells in the livers of L. chagasi-infected mice; (2) To investigate whether immunosuppressive mechanisms are overcome in lymphocytes of Brazilians who are immune to L. chagasi, either after recovery from VL or after subclinical infection, and in the livers of mice that are immunized against disease. We will identify recombinant L. chagasi T cell antigens that stimulate protective immune responses with IFN-g production in both hosts, in order to test these in mouse immunizations. We hypothesize that inhibition of IFN-g is a major means by which L. chagasi survive in liver granulomas of mice and in macrophages of humans with symptomatic VL. Our goal is to identify patterns of immunity that are parallel between these hosts, so that we can rationally evaluate human immunization strategies in mice. Critical for the success of the project is access to a population in a region of Brazil where infection with L. chagasi is common but other forms of leishmaniasis are rare. Our Brazilian collaborator Dr. Jeronimo provides this connection.
