A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2.
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.
Pridmore
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AC
Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, University of Sheffield, Sheffield, United Kingdom.
Wyllie
D H
DH
Abdillahi
F
F
Steeghs
L
L
van der Ley
P
P
Dower
S K
SK
Read
R C
RC
D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics*; D016207:Cytokines / Q000032:analysis*; D029721:Drosophila Proteins; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000032:analysis; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D009154:Mutation; D009345:Neisseria meningitidis / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D016207:Cytokines; D029721:Drosophila Proteins; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000217:Acyltransferases; C050304:acyl-(acyl-carrier-protein)-UDP-N-acetylglucosamine acyltransferase