NEUTRALIZATION OF RESPIRATORY VIRUS AT THE AIRWAY MUCOSA

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In the airway, resistance to respiratory viral infections best correlates with the presence of viral specific IgA antibodies in the mucosal secretions. IgA is transported through the epithelial lining cells of a mucous membrane by the polymeric immunoglobulin receptor (Pig-R) prior to secretion. Moreover, respiratory viruses replicate within these cells. Therefore, IgA may be able to complex with newly synthetized viral proteins within cells, effectively abort viral infection prior to viral shedding. The focus of this proposal is to explore this hypothesis by delineating this novel and previously undescribed mechanism by which IgA can neutralize virus at a mucosal surface. Four specific aims have been outlined. Initially, using IgA monoclonal antibodies against the viral structural proteins, the ability of IgA to interrupt replication of Sendai and Influenza viruses will be examined in Madin-Darby Canine Kidney epithelial cells which have been transfected with the CDNA for rabbit Pig-R. Secondly, both the optimal antigenic specificity of IgA and the most susceptible step in virus reproduction for intracellular neutralization will be determined. Thirdly, since Sendai and Influenza viruses have different modes of cell entry and replication, the ease with which IgA can interrupt their respective life cycles will be compared. Finally, to better replicate the natural biological environment, a rat tracheal epithelial cell line will be transfected with the cDNA for rat pIg-R and subsequently used as a model to study intracellular interaction between IgA and virus. The results of these studies will be used to design future experiments which will examine and compare the histopathological consequences of viral infection in an epithelial cell system in the presence of anti-viral antibodies of different classes and antigenic specificity. Information generated by these studies could contribute to the development of safe, effective anti-viral immunization protocols and to new approaches to the medical management of the sequelae of viral respiratory infections, including heightened airway reactivity.