STUDY OF NEISSERIA MENINGITIDIS LIPOOLIGOSACCHARIDE

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Meningococcal meningitis remains a significant health problem worldwide. The lipooligosaccharide (LOS) of N. meningitidis is a major component of the outer membrane and a major virulence factor. It has been shown that the oligosaccharide chain of LOS mimics human glycosphingolipid antigen on the surfaces of erythrocytes and other tissues. LOS expression in N. meningitidis is also subject to phase variation, which is related to the pathogenesis during the bacterial infection. A genetic locus called lgt encoding glycosyltransferase, responsible for the biosynthesis of oligosaccharide chain, was first identified in Neisseria gonorrhoeae and the lgt homologues have been sequenced for three strains of N. meningitidis, 126E (L1), MC58 (L3) and Z2491. No sequence information on the lgt locus is available for the other 9 immunotypes of N. meningitidis so far. Phase variation and stability in the expression of L8-LOS immunotype was observed in two N. meningitidis strains, M978 and A1. In order to understand the genetic basis of phase variation and stability, we have determined the nucleotide sequences of lgt locus from PCR products for theses two strains. Two novel genetic organizations have been identified in these two strains by comparing them to the lgt sequences of N. meningitidis and N. gonorrhoeae in the databases. Strain M978 contains 5 open reading frames that had homology to lgtC, A, B, E and a mosaic ORF consisted of the partial lgtA and lgtB at the 5'-end, whereas stain A1 contain only two genes included lgtA and lgtE. The data demonstrated that the lgt genetic components and arrangement is one of the important factors to determine phase variation and phase stability. DNA sequencing of lgt loci for other 9 immunotypes have been finished and the sequences are currently being evaluated. The further work is to construct a htrB mutant from a vaccine candidate strain OP-, a truncated LOS mutant of N. meningitidis M986-NCV, to reduce the toxicity of the LOS by removing two of fatty acids from lipid A.