Neisseria gonorrhoeae (the gonococcus) is the etiologic agent of gonorrhea. Gonorrhea, and its dramatically more serious complications, salpingitis and PID (pelvic inflammatory disease), which may lead to sterility and ectopic pregnancy, cost the US healthcare system over $1 billion in 1995. In the USA, gonorrhea and other sexually transmitted diseases (STDs) disproportionately affect young women and minority populations. No vaccine exists. Dr. Rest proposes to study the pathogenesis of gonococcal infection and disease to obtain a better understanding of gonorrhea and its complications, of other mucosal infections, and of other STDs. He will specifically investigate the interaction of gonococci with human epithelial cells and neutrophils, cells with which gonococci interact during infection and disease. The focused goal of this proposal is to better define the function of gonococcal Opa (opacity associated, outer membrane) proteins in their ability to mediate gonococcal adhesion to and entry into human cells.
Specific Aims 1 and 2 attempt to answer the questions, """"""""What part(s) of Opa proteins bind to their receptor(s) on human cells to induce uptake of gonococci?"""""""" Aim 1 - Investigate structure-gunction relationships of Opa proteins expressed in the outer membrane of E. coli. Molecular genetic, protein analytical, and immunologic approaches will be used, including mutation of opa genes, synthesis of Opa peptides, and production of anti-Opa antibodies. These reagents will be used to probe the interaction with human neutrophils and epithelial cells of E. coli expressing Opas.
Aim 2 - Use the knowledge gained and reagents developed in Aim 1 to better understand the molecular mechanisms of action of Opa proteins expressed within the gonococcal outer membrane. Mutated opa genes will be exchanged into the chromosome and expressed. In addition, to better define the molecular events in receptor-ligand interactions, we will further characterize the lectin-like interactions of Opa+ gonococci and purified Opa proteins with neutrophils and epithelial cells and their Opa receptors.
Aim 3 - Further characterize, identify and clone the gene for a putative '19 kD', granule-associated, neutrophil receptor for Opa proteins.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacteriology and Mycology Subcommittee 2 (BM)
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Hitchcock, Penelope
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Mcp Hahnemann University
Schools of Medicine
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Liu, Shi V; Saunders, Nigel J; Jeffries, Alex et al. (2002) Genome analysis and strain comparison of correia repeats and correia repeat-enclosed elements in pathogenic Neisseria. J Bacteriol 184:6163-73
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Rest, R F; Liu, J; Talukdar, R et al. (1994) Interaction of pathogenic Neisseria with host defenses. What happens in vivo? Ann N Y Acad Sci 730:182-96
Frangipane, J V; Rest, R F (1993) Anaerobic growth and cytidine 5'-monophospho-N-acetylneuraminic acid act synergistically to induce high-level serum resistance in Neisseria gonorrhoeae. Infect Immun 61:1657-66
Rest, R F; Frangipane, J V (1992) Growth of Neisseria gonorrhoeae in CMP-N-acetylneuraminic acid inhibits nonopsonic (opacity-associated outer membrane protein-mediated) interactions with human neutrophils. Infect Immun 60:989-97
Simon, D; Rest, R F (1992) Escherichia coli expressing a Neisseria gonorrhoeae opacity-associated outer membrane protein invade human cervical and endometrial epithelial cell lines. Proc Natl Acad Sci U S A 89:5512-6
Naids, F L; Rest, R F (1991) Stimulation of human neutrophil oxidative metabolism by nonopsonized Neisseria gonorrhoeae. Infect Immun 59:4383-90
Naids, F L; Belisle, B; Lee, N et al. (1991) Interactions of Neisseria gonorrhoeae with human neutrophils: studies with purified PII (Opa) outer membrane proteins and synthetic Opa peptides. Infect Immun 59:4628-35
Elkins, C; Rest, R F (1990) Monoclonal antibodies to outer membrane protein PII block interactions of Neisseria gonorrhoeae with human neutrophils. Infect Immun 58:1078-84

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