title: Activation of human meningeal cells is modulated by lipopolysaccharide (LPS) and non-LPS components of Neisseria meningitidis and is independent of Toll-like receptor (TLR)4 and TLR2 signalling.
abstract: The interactions of Neisseria meningitidis with cells of the meninges are critical to progression of the acute, compartmentalized intracranial inflammatory response that is characteristic of meningococcal meningitis. An important virulence mechanism of the bacteria is the ability to shed outer membrane (OM) blebs containing lipopolysaccharide (LPS), which has been assumed to be the major pro-inflammatory molecule produced during meningitis. Comparison of cytokine induction by human meningeal cells following infection with wild-type meningococci, LPS-deficient meningococci or after treatment with OM isolated from both organisms, demonstrated the involvement of non-LPS bacterial components in cell activation. Significantly, recognition of LPS-replete OM did not depend on host cell expression of Toll-like receptor (TLR)4, the accessory protein MD-2 or CD14, or the recruitment of LPS-accessory surface proteins heat shock protein (HSP)70, HSP90alpha, chemokine receptor CXCR4 and growth differentiation factor (GDF)5. In addition, recognition of LPS-deficient OM was not associated with the expression of TLR2 or any of these other molecules. These data suggest that during meningococcal meningitis innate recognition of both LPS and non-LPS modulins is dependent on the expression of as yet uncharacterized pattern recognition receptors on cells of the meninges. Moreover, the biological consequences of cellular activation by non-LPS modulins suggest that clinical intervention strategies based solely on abrogating the effects of LPS are likely to be only partially effective.
authors.affiliation: Molecular Microbiology, Division of Infection, Inflammation and Repair, University of Southampton Medical School, Southampton General Hospital, Southampton SO16 6YD, UK.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Humphries
authors.forename: Martha
authors.initials: M
authors.lastname: Triantafilou
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Makepeace
authors.forename: John E
authors.initials: JE
authors.lastname: Heckels
authors.forename: Kathy
authors.initials: K
authors.lastname: Triantafilou
authors.forename: Myron
authors.initials: M
authors.lastname: Christodoulides
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D031541:Fluorescence Resonance Energy Transfer; D055428:Growth Differentiation Factor 5; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000502:physiology*; D008579:Meningioma; D009154:Mutation; D009345:Neisseria meningitidis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014407:Tumor Cells, Cultured
chemical_list: D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016207:Cytokines; C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C495377:LY96 protein, human; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D019718:Receptors, CXCR4; 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