Pulmonary infection with the fungal pathogen, Pneumocystis jirovecii, is a common and often fatal complication of HIV infection. Emerging data suggest that Pneumocystis may also complicate lung diseases in non-HIV-infected hosts. The long-term goal of this Program Project is to develop a vaccine against Pneumocystis. To that end, we have identified a novel vaccine candidate for Pneumocysfis termed mini-kexin. We will identify mechanisms through which CD4+ T-lymphocytes participate in systemic and mucosal immune responses to the kexin vaccine. This project will test the experimental hypothesis that CD4+ T-lymphocyte help is necessary for optimal mucosal CD8+ T-cell and antibody responses to mini-kexin using a prime/boost vaccine strategy. The goal of these studies will be to define the role of CD4+ T-lymphocytes in vaccine responses in normal hosts. They are meant to complement experiments proposed for Project 2 that will focus on CD4-independent vaccine responses. In addition to mini-kexin, we will also investigate in our model systems antigen candidates identified through the Antigen Discovery Core. There are 4 Specific Aims: 1. To test the concept that CD4+ T-lymphocyte help is necessary during the priming phase of mini-kexin vaccination for optimal CD8+ and antibody responses in lung tissue. 2. To test the concept that T-lymphocyte CD40 ligand interactions are necessary for optimal CD8+ and antibody vaccine responses in lung tissue. 3. To test the concept that Stat3 and IL-17-secrefing T-lymphocytes are required for optimal CD8+ and antibody vaccine responses in lung tissue. 4. To validate the role of CD40+ and IL-17-secrefing T-lymphocytes in local vaccine responses of nonhuman primates.
The results of these experiments may lead to novel approaches to augment mucosal immunity against Pneumocystis in both immunocompetent and HIV-infected individuals. Collaborative experiments will extend selected results of these experiments to vaccination against tuberculosis in Project 3.
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