Genetic Basis for Biosynthesis, Structure, and Function of Meningococcal Lipooligosaccharide (Endotoxin)

Kahler, Charlene M.; Stephens, David S.

doi:10.1080/10408419891294216

Cited by 159 publications

(141 citation statements)

References 185 publications

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“…This was evidenced by the finding that O-deacylation of LOS significantly reduced the binding of TREM-2A to the three strains tested, indicating that the lipoidal moiety of the LOS dictates TREM-2A binding. Heterogeneity in the structure of gonococcal lipid A in terms of differences in the number of acyl groups (hexaacyl versus pentaacyl) as well as in the numbers of phosphate and phosphoethanolamine residues contained within the lipid A molecules expressed by each strain likely underlie the variability in the binding of TREM-2A to LOS (15,17). In contrast, we observed a significant difference in the binding of TREM-2A to 1291 and F62 LOS, both of which express a structurally identical OS α chain terminating in lacto-N-neotetraose (27).…”

Section: Discussionmentioning

confidence: 99%

“…Gonococcal LOS is structurally related to the lipopolysaccharide (LPS) expressed by enteric Gram-negative bacteria, although LOS does not possess the repeating O-polysaccharide regions (15,16). LOS is composed of a hydrophilic oligosaccharide core which is exposed on the surface, and a hydrophobic lipid A portion containing fatty acid residues that vary in acylation and phosphorylation which anchors the LOS into the bacterial outer membrane (17).…”

Section: Introductionmentioning

confidence: 99%

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TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells

et al. 2008

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Triggering receptor expressed on myeloid cells-2 (TREM-2) is an innate immune receptor that initiates cellular activation upon ligation. In this study, we examined the interaction of TREM-2 with Neisseria gonorrhoeae using murine TREM-2A as it has been reported to recognize bacterial ligands. Using a whole bacteria ELISA, TREM-2A bound to all 6 strains in variable degrees. Far western blots of gonococcal outer membranes revealed TREM-2A binding to lipooligosaccharide (LOS) and Opa protein with predominant binding to LOS. Binding of TREM-2A to LOS was confirmed by ELISA and surface plasmon resonance. O-deacylation of the lipid A significantly reduced binding. Flow cytometry and reporter cell assays showed that gonococci bound to TREM-2A-transfected cells and induced transmembrane signaling. In humans, TREM-2 was constitutively expressed by genitourinary and fallopian tube epithelial cells, both of which are primary targets of gonococcal invasion. Ligation of TREM-2 by LOS induced IL-6 production in HeLa cervical carcinoma cells. To our knowledge, this is the first report of the expression of human TREM-2 by cells deriving from a non-myeloid lineage. We conclude that gonococci can interact with TREM-2 receptors through binding to LOS and Opa protein and initiate cell signaling and cytokine production.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells

et al. 2008

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“…Meningococcal LOS and lipid A structures. A: NMB is complete LOS structure with an alpha lactoneotetraose oligosaccharide chain, a complete inner core and hexa-acylated, bisphosphorylated lipid A [46]; B: gmhB is truncated LOS structure composed only of KDO 2 -lipid A (hexa-acylated and bisphosphorylated) [47]; C: kdtA: is native hexa-acylated, bisphosphorylated lipid A structure [9]. Bioactivity of meningococcal LOS and unglycosylated lipid A structures.…”

Section: Discussionmentioning

confidence: 99%

TLR4-dependent adjuvant activity of Neisseria meningitidis lipid A

Zughaier

Steeghs

Ley³

et al. 2007

Vaccine

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The adjuvant activity of Neisseria meningitidis serogroup B lipopoly(oligo)saccharide (LOS) from wild-type and genetically-defined LOS mutants and unglycosylated meningococcal lipid A was assessed in C3H/HeN and C3H/HeJ mice. Meningococcal lipid A, a weak agonist for TLR4/MD-2 in human macrophages, was found to have adjuvant activity similar to that of wild-type and KDO 2 -lipid A LOS in C3H/HeN mice. All meningococcal LOS structures as adjuvants induced high titers of IgG1, IgG2a and IgG2b but very little IgG3 to OMP compared to no adjuvant PBS controls. In addition, induced OMP antibodies were shown to have high bactericidal activity against serogroup B meningococci. Purified LOS and lipid A structures failed to induce any adjuvant activity in C3H/ HeJ mice indicating that meningococcal LOS as an adjuvant was TLR4-dependent. Unglycosylated meningococcal lipid A because of its weak agonist activity for human macrophages and retention of adjuvant activity may be a candidate for use in serogroup B meningococcal OMP and OMV vaccines and for use as an adjuvant in other vaccines.

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“…The L3 immunotype has a similar ␣-chain but extended with a lacto-N-neotetraose unit, which can be further extended with a sialic acid residue. Meningococci are capable of sialylating the lacto-N-neotetraose unit by using endogenously produced CMP-NANA as substrate or by using this nucleotide sugar when added to the growth medium (24). The sialic acid residue can be removed from LPS with neuraminidase (25).…”

Section: Phenotype Of a Neisserial Imp Mutantmentioning

confidence: 99%

Identification of an outer membrane protein required for the transport of lipopolysaccharide to the bacterial cell surface

Bos

Tefsen

Geurtsen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

235

226

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Lipopolysaccharide (LPS), also known as endotoxin due to its severe pathophysiological effects in infected subjects, is an essential component of the outer membrane (OM) of most Gramnegative bacteria. LPS is synthesized in the bacterial inner membrane, a process that is now well understood. In contrast, the mechanism of its transport to the outer leaflet of the OM has remained enigmatic. We demonstrate here that the OM protein, known as increased membrane permeability (Imp) or organic solvent tolerance protein, is involved in this process. An Impdeficient mutant of Neisseria meningitidis was viable and produced severely reduced amounts of LPS. The limited amount of LPS that was still produced was not accessible to LPS-modifying enzymes expressed in the OM or added to the extracellular medium. We conclude therefore that Imp mediates the transport of LPS to the cell surface. The role of Imp in LPS biogenesis and its high conservation among Gram-negative bacteria make it an excellent target for the development of novel antibacterial compounds. G ram-negative bacteria are enclosed by a cell envelope consisting of an inner membrane (IM) and an outer membrane (OM), separated by the periplasm. The IM is a phospholipid bilayer, whereas the OM is an asymmetrical bilayer, containing phospholipids in the inner leaflet and lipopolysaccharide (LPS) in the outer leaflet. LPS consists of a hydrophobic membrane anchor, lipid A, substituted with a nonrepeating oligosaccharide, the core region. In many bacteria, the core region is extended with the O antigen, a repeating oligosaccharide. The lipid A-core region and the O antigen are synthesized as separate units at the cytoplasmic leaflet of the IM. Almost all of the enzymes involved in their biosynthesis have been identified in Escherichia coli (1, 2). The transport of the lipid A-core moiety to the periplasmic side of the IM is mediated by the MsbA protein, an ATP-binding cassette family transporter (3), whereas flipping of O antigen units over the IM can be facilitated by several distinct mechanisms (1). At the periplasmic side of the IM, the O antigen is ligated to the lipid A-core region. The next step, transport of the fully assembled LPS through the periplasm and across the OM, remains an entirely elusive aspect of LPS biogenesis (1, 2). Recently, Omp85, an essential OMP, was suggested to be involved in this process (4). However, we found a severe OMP assembly defect in a Neisserial Omp85 mutant (5). This phenotype, together with the affinity of Omp85 for OMPs (5) and the presence of omp85 homologs in Gram-negative bacteria lacking LPS, are much more consistent with a role of this protein in OMP assembly, with only an indirect role in LPS transport. Braun and Silhavy (6) identified another essential OMP in E. coli, depletion of which resulted in the formation of aberrant membranes. Missense mutations in the gene encoding this 87-kDa OMP, called increased membrane permeability (Imp) or organic solvent tolerance protein, were already known to affect OM permeability (7,8). He...

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Genetic Basis for Biosynthesis, Structure, and Function of Meningococcal Lipooligosaccharide (Endotoxin)

Cited by 159 publications

References 185 publications

TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells

TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells

TLR4-dependent adjuvant activity of Neisseria meningitidis lipid A

Identification of an outer membrane protein required for the transport of lipopolysaccharide to the bacterial cell surface

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