The objective of this application is to permit the applicant to develop expertise as an independent scientist in the field of Immunovirology in order to pursue medically relevant studies on the pathogenesis and control of viral infections. The general aim of the proposed project is to understand the pathogenesis, immunopathology and immune response to rotavirus infection using the murine model in order to answer the hypothesis: Rotavirus may induce virus specific cytotoxic immune responses, e.g., H-2 restricted cytotoxic T. lymphocytes, complement-dependent lytic antibodies, antibody-dependent cell-mediated cytotoxicity, and virus-induced but nonspecific effector lymphocyte responses (e.g., increased natural killer cell activity). If these responses occur, they may contribute to the control and/or to the pathology of rotavirus infections. Summary of Specific Aims 1. To standardize and expand the clinical parameters of the murine model of rotavirus infection in order to set the foundation for the remaining aims. 2. To characterize and assess the comparative levels of importance of the different limbs of the immune response to rotavirus infection. To accomplish this we will assess the humoral response at the local (GI) and systemic levels by standard immunoglobulin assays. We will develop cell cytotoxicity assays to assess the role of cellular immunity in this naturally occurring animal model. 3. To assess the roles of these immune responses in the immunopathology of this infection by challenge experiments of nude mice and their immunocompetent counterparts. 4. To assess the role of these immune responses in the protection against and recovery from rotavirus infection by antibody and lymphocyte transfer experiments. Long-term aims of this project which will extend beyon the 5 years of this research support are: 1. To determine the viral antigenic specificity of killing of rotavirus infected cells by these immune responses using monoclonal antibodies. 2. To analyze in detail the lymphocyte(s) responsible for recovery and/or immunopathology, using immunotherapy with cloned effector lymphocytes, e.g., Tc lymphocytes.
