Respiratory Syncytial Virus (RSV) is a major public health problem in virtually all parts of the world, with significant morbidity, and mortality in the immunocompromised host. No effective vaccine is currently available for human use. Although the infection is exquisitely restricted to the respiratory epithelium, the role of mucosal tissues in the mechanism of pathogenesis or protective immunity remains to be determined. The nature of interaction between the respiratory epithelium and the virus appears to be an important determinant of the outcome of infection, based on studies carried out during the current funding period. This renewal proposal will focus on three important areas of mucosal immunity to RSV. These include: 1) Role of respiratory epithelium in the pathogenesis of, and mucosal immune response to infection with RSV. It is proposed to characterize the synthesis and release of immunoregulatory and proinflammatory cytokines by virus infected respiratory epithelial cells, the antigen presenting structures expressed by respiratory epithelium which influence T cell activation after exposure to RSV, and the functional effects of T cells and eosinophils following their interaction with virus infected respiratory epithelial cells. 2) Effects of secretory IgA (sIgA) RSV antibody on uptake of RSV antigen and subsequent development of T cell responses and elimination of the virus infected cells. Studies will be undertaken to evaluate the efficiency of antigen presentation by MHC molecules in respiratory epithelium after exposure to RSV. We will examine the neutralizing antibody activity in RSV specific secretory IgA and evaluate the uptake and secretion of SIgA, polymeric IgA and other RSV specific immunoglobulin by respiratory epithelial cells, employing monoclonal antibodies to the whole virus and to F or G viral proteins. 3) Outcome of differential selection of various RSV antigen epitopes for T cell presentation, based on the lineage of mucosal antigen presenting cells (APC). Comparative studies will be carried out to define the antigen presenting potential of respiratory epithelium (the site of primary disease of RSV), other mucosal epithelial cells and conventional APC. It is proposed to define immunodominant epitopes within F and G proteins of RSV capable of stimulating T cell activation with different MHC alleles. Finally, studies will be carried but to examine the kinetics and repertoire of T cell specific responses to different RSV peptide immunogens. We hope that the studies proposed in this application will show how different components of the immunopathological response to RSV infection are associated with recognition of particular viral proteins expressed on the airway epithelium by specific cytotoxic and helper T cell subsets and how protective immunity can be induced without harmful secondary responses to RSV infection, thereby enhancing the development of a safe, effective vaccine.
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