Taking advantage of the interrelatedness of the different anatomic compartments of the mucosal associated lymphoid system, we aim to improve the efficiency and safety of oral (mucosal) immunization to achieve protective IgA based immune responses in the respiratory tract. The model system to be employed is Sendai virus infection of mice. Sendai virus, a parainfluenza virus and a natural mouse pathogen, has biologic and pathologic similarities to many respiratory viruses which cause moderate to severe disease in humans. We have shown previously, using cholera toxin as an oral adjuvant and a combination of oral and nasal immunization, that protection, which correlates with titers of virus-specific mucosal IgA in the respiratory tract, can be achieved against viral challenge. However, the immunization procedures require relatively large repeated doses of oral inactivated virus. In the present proposal we will investigate live attenuated strains of Salmonella bacteria expressing Sendai virus proteins as vectors for more efficient oral immunization. Salmonella naturally colonize the intestinal Peyer's patches and thus are a good candidate to deliver antigens to the body's largest concentration of mucosal lymphoid tissue from where the immune response can be disseminated to the respiratory tract. We will also investigate the duration of protection and immunologic memory induced by different strategies of mucosal immunization, e.g., with and without mucosal adjuvants, Salmonella as a mucosal vector, etc. Because immunization and infection with respiratory viruses can be associated with immunopathologic sequelae, we will investigate the immunopathologic consequences of different types of immunization, concentrating on immune complex mediated lung injury. We propose to study active immunization and infection to ascertain what types of immune responses predispose the host to immunologic injury. We also plan to use our well characterized IgA and IgG monoclonal anti-viral antibodies to define more precisely the nature of tissue-damaging immune complexes. Finally, in passive immunization experiments we will use the same well characterized anti-viral monoclonal antibodies to study the relative protective efficacies of different antibody isotypes. The research proposed has the potential to provide insights that lead to effective, new immunization strategies for preventing common human respiratory infections.
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