Neisseria gonorrhoea, the causative agent of gonorrhea, is one of the most prevalent diseases in this country. In addition to local infection, the gonococcus can cause serious complications, including pelvic inflammatory disease (PID), the leading cause of sterility in females in the U.S. Of the bacteria that are known to be etiologic agents in PID, N. gonorrhoea is the only one that is considered to be an obligate aerobe. However, we have shown that the gonococcus can grow anaerobically and that it regulates gene expression in response to the availability of oxygen, suggesting that anaerobic growth is of physiological significance to the gonococcus. Since N. gonorrhoea is isolated from mixed infections with facultative and obligate anaerobes, increases its oxygen consumption rates in the presence of human serum and cells, and sera from females with gonococcal infections contain antibodies to proteins anaerobically induced in vitro, it is likely that this organism grows anaerobically in vivo. This raises the possibility that the gonococcus has a virulence regulon that is induced during anaerobic growth.
Our specific aims are: I. To characterize the anaerobically induced proteins and their genes. We will clone the major anaerobically induced protein, Pan1, as it is a major antigen recognized by patient sera. The cloned gene will be sequenced, compared to sequences of genes with known functions, and will be used as a probe to determine the incidence of this gene among other Neisseria spp. Preliminary experiments suggest that meningococcal strains produce only small amounts or none of this protein. This would be the first example of a gonococcal protein that is not found in equal abundance in the meningococcus. II. To study the human immune response to gonococcal infection. We will test preinfection and post-infection sera and seminal plasma from a male volunteer infection study for the presence of antibodies to anaerobically induced proteins. This study will allow us to determine if the production of antibodies to Pan1 is the major response to gonococcal infection, as was suggested by our previous studies, and whether mucosal antibody to Pan1 is produced. III. To determine the role of anaerobically induced proteins in the virulence of N. gonorrhoea. We will use a model system for invasion of human cells as a measure of virulence of anaerobically vs. aerobically grown gonococci. We believe that the unusual delay in invasion seen by the gonococcus as compared to other invasive bacteria is due to a requirement for anaerobic induction of a virulence regulon. Mutants in the Pan1 gene, the gene for a putative activator protein required for induction of the anaerobic regulon, and other genes that are under the control of this activator will be assessed in the invasion model system to detect differences in virulence.
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