Moraxella (Branhamella) catarrhalis is now acknowledged to be an important cause of otitis media, or middle ear infection, in infants and young children and can also produce disease in the lower respiratory tract. Virtually nothing is known about M. catarrhalis virulence factors or about which surface antigens of this pathogen may be targets for antibodies protective against M. catarrhalis disease. Using an animal model, the applicant has identified two promising vaccine candidates among the surface-exposed proteins of this organism. Both the CopB major outer membrane protein and the UspA surface protein have been shown to be targets for monoclonal antibodies which, when used to passively immunize mice, enhance pulmonary clearance of M. catarrhalis. The applicant has identified a CopB epitope that binds the protective monoclonal antibody described above. In addition, the applicant has discovered that the UspA protein is most similar to the YadA virulence factor of pathogenic Yersinia species. The goal of this grant proposal is to expand upon these findings and investigate these macromolecules as potential vaccine candidates. The first Specific aim involves determination of the functional role of the UspA protein. Specifically, the applicant will use mutant analysis to determine whether this protein is a virulence factor for M. catarrhalis. The second Specific Aim will involve determination of whether CopB- and UspA-derived peptides can induce the synthesis of antibodies that are biologically active against M. catarrhalis. This biological activity will be assessed in bactericidal activity assays and in the pulmonary clearance system. The third Specific Aim involves the use of recombinant forms of the CopB and UspA proteins for testing as experimental vaccinogens. These purified, intact proteins will be tested for their ability to induce the synthesis of biologically active antibodies. The results of these experiments will provide important information about the suitability of CopB and UspA for vaccine development.
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