T CELL RESPONSES TO INTRACELLULAR BACTERIAL PATHOGENS

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DESCRIPTION (Adapted from the Investigator's abstract): There is considerable interest in understanding the role of the host immune response in the clearance of an infectious agent. Such information is relevant to the understanding of disease processes and to the development of effective vaccine strategies. Moreover, such studies can provide basic insights into the mechanisms by which prior exposure to an infectious agent is linked to the development of autoimmune disease. This project describes studies designed to identify and characterize the specific CD8+ T-cell response generated following infection with the Gram negative enteric pathogen, Salmonella typhimurium. Preliminary data have been generated in a murine model demonstrating that following system challenge with Salmonella typhimurium, mice generate a potent CD8+ T-cell response specific for Salmonella-infected cells. This response is CD8 dependent and can recognize targets in a H-2 non- restricted fashion. Furthermore, the non-MHC restricted component of the Salmonella specific CD8 T-cell response recognize targets in a Tap dependent fashion. Based on the preliminary data, the following Specific Aims are proposed: 1. Characterization of Salmonella-specific CD8+ CTLs following in vivo challenge with live virulent S. typhimurium. 2. Examination of the contribution of CD8+ CTLs in limiting virulent Salmonella infections. 3. Characterization and identification of epitopes recognized by Salmonella-specific CTLs. 4. Design and evaluate vaccination strategies targeting Salmonella epitopes that could evoke protective immunity to a challenge with virulent S. typhimurium. This information will impact on our understanding of the role of CD8+ T-cells in the protective immune response to a major family of pathogens (Gram- negative bacteria) and also aid in the design of effective vaccines capable of inducing long-term protective immunity to enteric pathogens. In addition, such studies may facilitate the identification of self proteins cross-reactive with bacterial antigens that may play a role in the induction of autoimmune processes.