MOLECULAR IMMUNE RESPONSE DETERMINANTS OF RUBELLA VIRUS

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Our ultimate goal is to determine how aberrant immune responses to rubella virus contribute to the clinical and pathological manifestations of the congenital rubella syndrome, progressive rubella panencephalitis, vaccine arthralgia and perhaps rheumatoid arthritis and multiple sclerosis. A prerequisite is the construction of the molecular topography of the antigenic domains of rubella virus which elicit humoral and cell-mediated immune responses. This will provide the required data base to define the predicted alterations in the human immune response which contribute to the diverse complications of rubella. This project will define the minimum domains of rubella virus that are required to induce antibody responses which interrupt virus infectivity, and those amino acid sequences of the structural proteins which are processed and presented by human monocytes to establish cellular immunity. A library of monoclonal antibodies to rubella virus will be expanded and used to define both sequential and conformation- dependant antigen bearing domains residing on the structural polypeptides. These experiments will utilize novel approaches which combine the power of immunoprecipitation, antibody protected partial proteolytic digestion, SDS-PAGE and fast atom bombardment mass spectrometry. In vitro proliferative assays which use polypeptides or their fragments bound to particulate nitrocellulose will define antigenic domains recognized by immune cells. Selected synthetic oligopeptides will confirm the importance of these domains and provide reagents with which to probe critical differences between normal and anomalous responses in rubella related syndromes. The knowledge gained will increase our understanding of normal immune responses to this common human pathogen, provide critical information of use in constructing molecularly engineered vaccines, facilitate the approach of others to this general problem, and provide better insight into aberrant human immune responses and their contribution to viral persistence and virus-induced immunopathology.