LIPOOLIGOSACCHARIDE BIOSYNTHESIS IN NEISSERIACEAE

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N. Gonorrhoeae and N. Meningitidis are important human pathogens. There are many more cases of gonorrhea then meningococcal meningitis, but meningitis is a much more serious disease due to the associated mortality. An effective vaccine would prevent the morbidity and mortality caused by these diseases and reduce the associated health care costs. Vaccine development has been hampered for a variety of reasons. It is not clear what role individual components play in the disease process, nor what components elicit a cross-reactive protective immune response. Studies on virulence determinants in these organisms are further hampered by the fact that these pathogens undergo both antigenic and phase variation of their surface antigens. Antigenic variation has obfuscated data obtained from many studies in the past because the cell surface of the organisms under study may have changed over the course of the study. The importance of lipooligosaccharide (LOS) in the pathogenesis and immunobiology of these organisms is unquestioned. LOSs are a family of complex macromolecules possessing many antigenic determinants that are important in natural and acquired immunity. LOS from N. Gonorrhoeae and N. Meningitidis are similar, both in composition and primary structure. They share antigenic properties with several of the nonpathogenic Neisseria sp. The variation of LOS in size, as measured by mobility on SDS-PAGE gels, is due to differences in the number of glycose units, 2- keto-3-deoxyoctonates (KDO), and/or hexosmines. Antigenic differences between strains can also result from substitutions of various glycose units or alterations of the linkages that connect the sugars. An understanding of the genetics of LOS biosynthesis is important if we are to define the conformations that stimulate disease symptoms and/or generate protective immune responses. Understanding the immunobiology of LOS may lead to the development of vaccines in a manner similar to what has been done with other organisms. The overall hypotheses to be tested are: "Can one construct strains with defined LOS structures?", "Can one use strains with defined LOS structures to determine the role that these components play in the disease process?"; and "Can one use these strains to induce a protective immune response - in humans?" These hypotheses will be tested using a molecular genetic approach.