Trypanosoma cruzi is the protozoan agent of Chagas disease, a major public health problem in Latin America. This parasite is transmitted to humans when insect-derived metacyclic trypomastigotes (IMT), the natural infective form of T cruzi present in excreta of the reduviid vector, contact mucosal surfaces or breaks in the skin. Systemic administration of recombinant IFN-gamma has been shown to increase resistance in mice during acute infection with the Talahuen strain of T. curzi. The focus of this research proposal is an evaluation of the importance of antigen specific IFN-gamma responses in resistance to T. cruzi infection and disease after a mucosal challenge with Tulahuen strain IMT. Three principal hypotheses will be tested: 1. The production of antigen specific IFN-gamma by CD4+ T lymphocytes is an important mechanism of resistance against T cruzi. The susceptibility of mice immunized with a protocol that induces Th1 cells will be compared with the susceptibility of mice immunized with a protocol that induces Th2 cells. The susceptibility of normal and SCID mice adoptively transferred with Th1 cells will be compared with other groups injected with Th2 cells. animals protected by immunization or adoptive transfer will be treated with a monoclonal antibody that neutralizes the biologic activity of IFN-gamma to determine if this cytokine is the crucial factor important for the resistance. 2. Immunications with recombinant parasite antigens that induce IFN- gamma responses protect against T. cruzi infection. A novel cDNA screening approach will b e used to identify new cDNAs that encode antigens capable of inducing IFN-gamma production by CD4+ Th1 lymphocytes. Recombinant antigens found to stimulate IFN-gamma responses will be used to immunize mice. Mice immunized with these recombinant antigens will be challenged orally with IMT to determine if they are protected against chronic T. cruzi infection. 3. T. cruzi specific IFN-gamma responses are not involved in the immune mediated pathology of chagasic cardiomyopathy. Mice immunized with vaccination protocols that promote optimal T. cruzi specific induction of IFN-gamma, and mice adoptively transferred with T. cruzi specific Th1 cells, will be investigated for the development of cardiac inflammatory lesions. Experimental protocols found to induce cardiac lesions will be studied further to determine if neutralization of IFN-gamma prevents the development of pathology.
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