Invasive diseases resulting from infections by pathogenic Neisseria are significant causes of morbidity and mortality among women of child-bearing age and in pediatric populations. Efforts to control these diseases by vaccination have proven ineffective for N. gonorrhoeae infections and only partially successful for N. meningitidis infections. This lack of efficacy results mainly from the fact the antigenically conserved, immunogenic macromolecules capable of inducing broadly protective immunity have not been identified. Outer Membrane Protein - Macromolecular Complex (OMP-MC) is a surface component of Neisseria that fulfills many of the requisite properties for a neisserial vaccine antigen, including conservation of structure and antigenicity, surface exposure, and the ability to induce both bactericidal and opsomic antibody responses. This proposal involves the confirmation that OMP-MC is accessible on bacterial surfaces both in vitro and in vivo and characterization of OMP-MC at the molecular level in order to delineate the potential role of OMP-MC in the pathogenesis of neisserial infections, to identify the OMP-MC epitopes responsible for the bactericidal, opsonic and/or protective reactivities of anti-OMP-MC antibodies and to define more accurately the degree of conservation of peptide structure among diverse neisserial strains and species.
These aims will be accomplished by immunoelectron microscopic evaluation of the reactivities of anti-OMP-MC antibodies with organisms from genital specimens as well as laboratory strains, by generating OMP-MC expression mutants by transposon-mediated and site-directed mutagenesis, by testing the pathogenicity of these mutants, especially gonococcal mutants, in a murine model of invasive neisserial infection, by determining the protective efficacies of bactericidal and opsonic antibodies in this bacteremia model, by fine structure mapping of linear epitopes using synthetic peptides and of conformational epitopes using OMP-MC internal deletion mutants, and by cloning and sequencing the omc genes encoding OMP- MC from diverse neisserial species including gonococcal, meningococcal and commensal representatives. The results of these studies will help identify potential antigenic structures for the immunoprophylaxis of invasive neisserial infections.
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