Despite the development of capsular vaccines, our understanding of the pathobiology of Neisseria meningitidis is incomplete, and the meningococcus remains an important worldwide pathogen. The surface glycolipids or lipooligosaccharides (LOS) are important in the pathogenicity of the meningococcus. The LOS are also immunogenic in humans and play a role in the development of natural immunity to the meningococcus. The meningococcal capsular vaccines that are currently available have limitations. For this reason, noncapsular surface antigens (including outer-membrane proteins, detoxified LOS and OS-protein conjugates) have been considered as alternative meningococcal vaccine candidates. The goal of this project is to characterize the structure of meningococcal lipooligosaccharides (LOS) and to characterize the expression of LOS epitopes during growth of the organism. The LOS of N. meningitidis are composed of multiple components which are antigenically and therefore structurally distinct. Recent advances in mass spectrometry have facilitated the structural analysis of the LOS of another closely related neisserial species, N. gonorrhoeae. The surface expression of LOS epitopes may vary within a population of meningococci and during growth of the organism. These changes may alter the susceptibility of Neisseria to lysis by human serum. Recently, the LOS of group A meningococci have been characterized using monoclonal antibodies (cAbs). A conserved LOS epitope (found on all group A, and some B and C meningococci) and LOS serotype-specific epitopes have been identified. During the next five years we will use two approaches to study and determine the structural basis of the antigenically conserved and serotype-specific regions of group A meningococcal LOS. We will examine the effects of chemical and enzymatic degradation techniques on the preservation of LOS epitope expression using gel electrophoresis and immunoblots. The preservation or disappearance of specific LOS epitopes after chemical/enzymatic modification will provide insight into the LOS structure and requirements for effective epitope expression. We will also examine the structure of the oligosaccharide portion (OS) of group A meningococcal LOS will be determine by composition and linkage analysis, and mass spectrometry. These studies should yield important information about the chemical requirements for expression of the serotype and conserved meningococcal lOS epitopes. We will also study the variability of expression of LOS epitopes in vitro within a population of meningococci during growth using fluorescence-activated cell sorting, immune electronmicroscopy, gel electrophoresis and immunoblots. These series of experiments should provide an increased understanding of the structure, expression, and biosynthesis of meningococcal LOS.
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