title: Complement activation and complement-dependent inflammation by Neisseria meningitidis are independent of lipopolysaccharide.
abstract: Fulminant meningococcal sepsis has been termed the prototypical lipopolysaccharide (LPS)-mediated gram-negative septic shock. Systemic inflammation by activated complement and cytokines is important in the pathogenesis of this disease. We investigated the involvement of meningococcal LPS in complement activation, complement-dependent inflammatory effects, and cytokine or chemokine production. Whole blood anticoagulated with lepirudin was stimulated with wild-type Neisseria meningitidis H44/76 (LPS+), LPS-deficient N. meningitidis H44/76lpxA (LPS-), or purified meningococcal LPS (NmLPS) at concentrations that were relevant to meningococcal sepsis. Complement activation products, chemokines, and cytokines were measured by enzyme-linked immunosorbent assays, and granulocyte CR3 (CD11b/CD18) upregulation and oxidative burst were measured by flow cytometry. The LPS+ and LPS- N. meningitidis strains both activated complement effectively and to comparable extents. Purified NmLPS, used at a concentration matched to the amount present in whole bacteria, did not induce any complement activation. Both CR3 upregulation and oxidative burst were also induced, independent of LPS. Interleukin-1beta (IL-1beta), tumor necrosis factor alpha, and macrophage inflammatory protein 1alpha production was predominantly dependent on LPS, in contrast to IL-8 production, which was also markedly induced by the LPS- meningococci. In this whole blood model of meningococcal sepsis, complement activation and the immediate complement-dependent inflammatory effects of CR3 upregulation and oxidative burst occurred independent of LPS.
authors.affiliation: Department of General Internal Medicine, University Medical Centre St. Radboud Nijmegen, Nijmegen, The Netherlands. t.sprong@aig.umcn.nl
authors.forename: Tom
authors.initials: T
authors.lastname: Sprong
authors.forename: Anne-Sophie W
authors.initials: AS
authors.lastname: Møller
authors.forename: Anna
authors.initials: A
authors.lastname: Bjerre
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wedege
authors.forename: Peter
authors.initials: P
authors.lastname: Kierulf
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Petter
authors.initials: P
authors.lastname: Brandtzaeg
authors.forename: Marcel
authors.initials: M
authors.lastname: van Deuren
authors.forename: T E
authors.initials: TE
authors.lastname: Mollnes
mesh_terms: D003167:Complement Activation; D003165:Complement System Proteins / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008589:Meningococcal Infections / Q000503:physiopathology*; D008954:Models, Biological; D009345:Neisseria meningitidis / Q000472:pathogenicity*; D016897:Respiratory Burst; D018805:Sepsis / Q000503:physiopathology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D003165:Complement System Proteins