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We incubated representative<jats:italic>Neisseria meningitidis<\/jats:italic>serogroup B (ST-32) and serogroup C (ST-11) strains and a lipopolysaccharide (LPS)-deficient mutant (the 44\/76<jats:italic>lpxA<\/jats:italic>mutant) in human serum and whole blood and measured complement activation and cytokine secretion and the effect of blocking these systems. HEK293 cells transfected with Toll-like receptors (TLRs) were examined for activation of NF-\u03baB. The threshold for cytokine secretion and activation of NF-\u03baB was 10<jats:sup>3<\/jats:sup>to 10<jats:sup>4<\/jats:sup>meningococci\/ml. LPS was the sole inflammation-inducing molecule at concentrations up to 10<jats:sup>5<\/jats:sup>to 10<jats:sup>6<\/jats:sup>meningococci\/ml. The activation was dependent on TLR4-MD2-CD14. Complement contributed to the inflammatory response at \u226510<jats:sup>5<\/jats:sup>to 10<jats:sup>6<\/jats:sup>meningococci\/ml, and complement activation increased exponentially at \u226510<jats:sup>7<\/jats:sup>bacteria\/ml. Non-LPS components initiated TLR2-mediated activation at \u226510<jats:sup>7<\/jats:sup>bacteria\/ml. As the bacterial concentration exceeded 10<jats:sup>7<\/jats:sup>\/ml, TLR4 and TLR2 were increasingly activated, independent of CD14. In this model mimicking human disease, the inflammatory response to<jats:italic>N. meningitidis<\/jats:italic>was closely associated with the bacterial concentration. Therapeutically, CD14 inhibition alone was most efficient at a low bacterial concentration, whereas addition of a complement inhibitor may be beneficial when the bacterial load increases.<\/jats:p>","DOI":"10.1128\/iai.00195-08","type":"journal-article","created":{"date-parts":[[2008,7,1]],"date-time":"2008-07-01T00:34:04Z","timestamp":1214872444000},"page":"4183-4189","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":39,"title":["Stages of Meningococcal Sepsis Simulated In Vitro, with Emphasis on Complement and Toll-Like Receptor Activation"],"prefix":"10.1128","volume":"76","author":[{"given":"Bernt Christian","family":"Hellerud","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Ulleva\u030al University Hospital, and University of Oslo, Oslo, Norway"},{"name":"Institute of Immunology, Rikshospitalet University Hospital, and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f8rgen","family":"Stenvik","sequence":"additional","affiliation":[{"name":"Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terje","family":"Espevik","sequence":"additional","affiliation":[{"name":"Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Lambris","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Chemistry, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom Eirik","family":"Mollnes","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Rikshospitalet University Hospital, and University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petter","family":"Brandtzaeg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ulleva\u030al University Hospital, and University of Oslo, Oslo, Norway"},{"name":"Faculty of Medicine, University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031076"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/338269"},{"key":"e_1_3_2_4_2","first-page":"427","year":"2006","unstructured":"Brandtzaeg, P. 2006. Pathogenesis and pathophysiology of meningococcal disease, p. 427-480. In M. Frosch and M. Maiden (ed.), Handbook of meningococcal disease. Wiley-VCH Verlag, Weinheim, Germany.","journal-title":"Handbook of meningococcal disease"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115660"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/159.2.195"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/160.1.58"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/166.3.650"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.16.10689"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm9806594"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/515176"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcibr022995"},{"key":"e_1_3_2_13_2","first-page":"44","volume":"86","year":"2002","unstructured":"Hackett, S. 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