LIPOOLIGOSACCHARIDE BIOSYNTHESIS IN NEISSERIACEAE

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Neisseria gonorrhoeae is responsible for over l million cases of gonorrhea each year, and the total health care costs associated with treating gonorrhea and complications that arise from infections caused by this organism exceed l billion dollars per year. A closely related pathogen, N. meningitidis, causes significant morbidity and mortality worldwide. If effective vaccines to prevent these diseases were available, health care costs would be dramatically reduced. The gonococcus possesses a wide variety of surface structures that can serve as virulence determinants for pathogenesis. Lipooligosaccharide (LOS) is the least understood cell surface antigen, both chemically and genetically, even though these molecules mediate most of the toxic damage in fallopian tubes, are responsible for complement activation on the cell surface, and serve as the target for bactericidal antibody. Furthermore, antibody directed against lipopolysaccharide is protective for a variety of Gram-negative infections. A vaccine that stimulated an anti-LOS response might be protective for both gonococcal and meningococcal infections. Since gonococcal and meningococcal LOS share many epitopes, and all of the genes that have been identified that are involved in LOS biosynthesis are conserved in both species, information gleaned about LOS biosynthesis in one species will be directly applicable to the other. This proposal will focus on LOS biosynthesis in the gonococcus. It will identify by gene cloning and genetic complementation techniques, genes required for LOS biosynthesis, characterize the genes by DNA sequence analysis, define the biochemical properties of the gene products and determine the mechanisms by which the gonococcus regulates their synthesis. If LOS is to be exploited as a vaccine candidate, we need to have strains of the gonococcus that stably produce the desired epitopes. Since the gonococcus can vary its LOS, depending on the host, and local environment, studies on the genetic regulation of its synthesis are warranted. Well defined, stable LOS producing strains are needed if we are to dissect the role of LOS in the disease process. By understanding how the gonococcus makes LOS, it will be possible to construct strains with defined LOS. These strains will be the basis of future studies into the role of LOS in the disease process.