Approximately 8-20 million individuals are infected with T. cruzi, leading to 20-50,000 deaths per year. No Chagas vaccines are available, and current drugs are only partially effective and associated with serious side effects. Further immunological research in the murine T. cruzi infection model is needed to define optimal targets for preventative vaccines and for immunotherapies designed to prevent/reverse chagasic disease pathology. T. cruzi-specific CD4+ Th1 cells (producing IFN-?, TNF-? and IL-2) are important for protective mucosal and systemic immunity against parasite invasion and dissemination, respectively. However, Th1 cells alone cannot transfer protection. Therefore, additional subsets of CD4+ T cells are necessary for optimally protective T. cruzi immunity. Recently identified Th17 cells (producing IL-17) protect against extracellular pathogens, but may also mediate immunopathology. Both intracellular and extracellular life stages maintain mammalian T. cruzi infection, and chagasic cardiomyopathy is caused by immunopathologic responses directed against chronic parasite infection. Th17 cells could be important for protection against the T. cruzi life stages present in infected hosts, and/or for development of chronic Chagas disease. This project will define the roles of Th1 and Th17 cells for T. cruzi immunity and immunopathology. Our extensive experience with the murine T. cruzi infection model, and our successful generation of T. cruzi- specific TCR transgenic mice will greatly facilitate these studies. We will test the following hypotheses: 1) To confirm the hypothesis that Th17 cells are important for protective T. cruzi immunity. 2) To test the hypothesis that Th17 cells are important for chronic chagasic immunopathology. These studies will provide critical information for T. cruzi vaccine development, and have broader significance regarding the importance of Th1 and Th17 cells in protective immunity and immunopathology during chronic infection.
Trypanosoma cruzi infection causes significant morbidity and mortality worldwide, and there are no highly effective drugs or vaccines. We propose to study the roles of 2 different subsets of CD4+ T cells (Th1 making IFN-? and Th17 making IL-17) in both protective immunity and chronic disease-associated immunopathology. The results of this work could lead to the development of protective and safe T. cruzi vaccines, immunotherapies capable of preventing or treating chagasic disease, and a better understanding of the general importance of these T cell subsets for other chronic diseases associated with immunopathology.
