Genetic basis for biosynthesis, structure, and function of meningococcal lipooligosaccharide (Endotoxin)

The exclusive human pathogen Neisseria meningitidis expresses lipooligosacc haride (LOS), an endotoxin that is structurally distinct from the lipopolys accharides (LPS) of enteric Gram-negative bacilli. Differences that appear to be biologically important occur in the composition and attachment of acy l chains to lipid A, phosphorylation patterns of lipid A, and the incorpora tion and phosphorylation of sugar residues in the LOS inner core. Further, unlike most enteric LPS, only two to five sugar residues are attached to th e meningococcal LOS inner core, and there are no multiple repeating units o f O-antigens. In contrast to Escherichia coli, where the LPS biosynthesis g enes are organized as large operons, the meningococcal LOS biosynthesis gen es are organized into small operons or are located individually in the chro mosome. Some of these genetic loci in meningococci and gonococci display po lymorphisms caused by localized chromosomal rearrangements. One mechanism o f antigenic variation of meningococci LOS is the regulation of glycosyltran sferase activity by slipped strand mispairing of homopolymeric tracts withi n the 5' end of the genes encoding these enzymes, resulting in the addition of different sugar residues to the LOS molecule. Meningococcal LOS is a cr itical virulence factor in N. meningitidis infections and is involved in ma ny aspects of pathogenesis, including the colonization of the human nasopha rynx, survival after bloodstream invasion, and the inflammation associated with the morbidity and mortality of meningococcemia and meningitis. Meningo coccal LOS, which is a component of serogroup B meningococcal vaccines curr ently in clinical trials, has been proposed as a candidate for a new genera tion of meningococcal vaccines. The rapidly expanding knowledge of the gene tic basis for biosynthesis, structure, and regulation of meningococcal LOS provides insights into unique endotoxin structures and the precise role of LOS in the pathogenesis of meningococcal disease.