The overall objective of the program is to understand key aspects of immunity to respiratory viruses at the cellular and molecular levels, with the long-term goal of developing novel approaches to immunization and therapy. The analysis concentrates on parainfluenza type 1 viruses that are natural pathogens of young children (hPIV-1) and laboratory mice (Sendai virus). These two viruses are approximately 72% homologous for the genes that have been sequenced so far, and show evidence of extensive crossneutralization. The basic approach is to utilize Sendai virus infection in the mouse for the experimental analysis of questions that cannot be addressed adequately for hPIV-1 in humans. The emphasis over the first 5 years will be to define the nature of the molecular interactions between viral proteins/peptides and virus specific immunoglobulin (Ig) molecules (Projects 1 and 5) and T cells (Projects 2 and 3), to characterize the cellular mechanisms promoting recovery from acute infection (Project 3), and to establish the parameters that are central to immunological memory and resistance to re-infection for both B (Projects 1 and 5) and T lymphocytes (Projects 2 and 4). Projects 1 and 2 will concentrate on hPIV-1, while Projects 3-5 will be largely concerned with Sendai virus. The program draws together 5 investigators from the Departments of Immunology, and Virology and Molecular Biology at St Jude Children's Research Hospital. This group has the conceptual and technical breadth to bring a broad range of contemporary virology and immunology approaches to bear on the general problem of host response and resistance to respiratory virus infection. Thus, questions concerning mechanisms that arise from the definition of T cell memory and specificity to hPIV-1 in humans will be analyzed in mice with Sendai virus. Findings on structure-function relationships and B and T lymphocyte repertoire usage from molecular and cellular analysis in vitro will be tested in vivo for biological relevance. The insights that are generated by this interactive, multidisciplinary approach will provide both a substantial basis for the later development of new ways to ameliorate these disease processes, and excellent focus for introducing young investigators to the complex and important area of viral immunity.
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