Recognition of bacterial lipopolysaccharide (LPS) is critical in the host defence against Gramnegative infection. While enterobacterial LPS signals via Toll-like receptor 4 (TLR4), it has recently been reported that the LPS of Leptospira interrogans, Legionella pneumophila, Rhizobium species Sin-1 and at least one strain of Porphyromonas gingivalis are capable of signalling via TLR2. Using a TLR transfection assay and measurement of an NF-kB-sensitive promoter region, the results show that the LPS of Bacteroides fragilis NCTC-9343, Chlamydia trachomatis LGV-1 and Pseudomonas aeruginosa PAC-611 also signal via TLR2 and it is pointed out that all TLR2-signalling LPS discovered to date demonstrate relatively weak endotoxicity in some models and structural features distinct from those LPS shown to signal via TLR4.

Meningococcal disease severity correlates with circulating concentrations of lipopolysaccharide (LPS) and proinflammatory cytokines. Disruption of the lpxA gene of Neisseria meningitidis generated a viable strain that was deficient of detectable LPS. The potency of wild-type N. meningitidis to elicit tumor necrosis factor (TNF)-alpha production by human monocyte-derived macrophages was approximately 10-fold greater than that of the lpxA mutant. Killed wild-type N. meningitidis and its soluble products induced interleukin (IL)-8 and TNF-alpha secretion by transfected HeLa cells expressing Toll-like receptor (TLR) 4/MD2, but the lpxA mutant was inactive via this pathway. In contrast, both strains induced IL-8 promoter activity in TLR2-transfected HeLa cells. These data provide evidence that N. meningitidis contains components other than LPS that can elicit biological responses via pathways that are independent of the TLR4/MD2 receptor system, and TLR2 is one of these alternate pathways. These findings have implications for future therapeutic strategies against meningococcal disease on the basis of the blockade of TLRs and the modulation of LPS activity.

Lipooligosaccharide (LOS) structure and capsular polysaccharide of Neisseria meningitidis each greatly influence the virulence of the organism and the quality of host innate immune responses. In this study, we found that production of the proinflammatory cytokine tumor necrosis factor (TNF) by a human monocytederived cell line (THP-1) exposed to strains of N. meningitidis lacking capsule and/or with truncated LOS was similar to that elicited by the isogenic wild-type strain. These mutants also exhibited no difference in induction of the interleukin-8 (IL-8) promoter in a transfected HeLa cell system of Toll-like receptor 2 (TLR2) and TLR4/MD2 signaling. However, purified LOS from diverse strains of Neisseria (both N. meningitidis and N. gonorrhoeae) caused widely variant levels of IL-8 promoter induction in cells expressing MD2 that correlated with the production of TNF from THP-1 cells. These data suggest that although modification of the oligosaccharide chain of LOS and/or absence of capsule do not affect cell signaling mediated by TLR4/MD2, finestructural differences in the LOS do influence signaling through TLR4/MD2 and, through this pathway, influence some of the proinflammatory responses elicited by Neisseria.Neisseria meningitidis is an important cause of sepsis syndrome and meningitis, the severity of which is correlated with the release of proinflammatory cytokines (50, 51). The lipooligosaccharide (LOS) of N. meningitidis, like other gram-negative bacteria, is a potent stimulator of the proinflammatory response, and plasma LOS levels correlate with the severity of disease (3). Neisserial LOS is composed of a hydrophobic lipid A portion that anchors it to the bacterial outer membrane, and this is linked to a hydrophilic oligosaccharide core, which is exposed on the surface. However, it does not possess the repeating O-polysaccharide region that is seen in the lipopolysaccharide (LPS) of many other bacteria. The outer core of the LOS is highly variable, and this forms the basis of strain immunotyping (41). The lipid A structure of both N. meningitidis (29) and N. gonorrhoeae (44) consists of a ␤-D-glucosaminyl-(1Ј36)-D-glucosamine disaccharide backbone with variable patterns of phosphorylation and fatty acid acylation (23).Addition of sialic acid to the terminal galactose moiety of the lacto-N-neotetraose of meningococcal LOS and the polysialic acid capsule of serogroup B organisms both determine virulence through the regulation of complement (10,20,22) and also by modification of a number of innate host immune responses, including expression of phagocyte adhesion molecules (26) and nonopsonic macrophage phagocytosis of the organism (38).The Toll-like receptors (TLRs) have been shown to initiate innate proinflammatory signal transduction in response to a number of pathogen-associated molecular patterns (33,34,39). TLR4, with its cofactor MD2, has been shown to respond to LPS (30,42), and TLR2 responds to lipoproteins (2) and peptidoglycan (45). TLR3, TLR5, and TLR9 respond to double-stranded RNA (1), fla...