Trypanosoma cruzi is an obligate intracellular protozoan parasite and causative agent of human Chagas' disease. Control of T. cruzi infection in mammalian hosts is heavily dependent on the generation of a class I MHC-restricted CD8+ T cell response to the parasite. During the initial project period the investigator has shown that T. cruzi infected host cells process and present parasite encoded molecules via class I MHC to CD8+ T cells and identified three T. cruzi CTL target molecules which are recognized by mice and humans infected with T. cruzi. Transfer of CD8+ T cells specific for these CTL epitopes or vaccination of mice to induce responses to these target molecules provides protection in susceptible mice. The proposed studies will build upon these results to determine the effector function of anti-T. cruzi CD8+ T cells and to evaluate the vaccine potential of CTL target molecules. The role of perforin/granzyme and Fas/FasL mediated lytic mechanisms and cytokine production in CD8+ T cell mediated protection will be determined. Special attention will be paid to the contribution of induction of nitric oxide production in host cells to the anti T cruzi CD8+ T cell response. Additional CTL target molecules will be identified, focusing on GPI-anchored amastigote surface proteins. LC/MS/MS analysis of MHC-associated peptide from T.cruzi-infected host cells will also be used to identify and evaluate potential targets of the CD8+ T cell response. CTL target molecules identified previously and during the course of future studies will be tested for their vaccine potential using peptide immunization, vaccination with recombinant vaccinia viruses and genetic immunization with DNAs. Lastly the possibility that members of the T. cruzi trans-sialidase family function as both targets and as inhibitors of the T. cruzi specific CD8+ T cell response by generating antagonist altered peptide ligands of CD8+ T cells will be ascertained. The completion of this project could provide the information and the tools necessary to determine whether or not targets of the anti-T. cruzi CTL response would be useful as vaccines.
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