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Physicochemical characterization and biological activity of lipooligosaccharides and lipid A from Neisseria meningitidisDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA, szughai{at}emory.edu
Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, Borstel, Germany
Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, Borstel, Germany
Institut für Physikalische Chemie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany
European Molecular Biology Laboratory c/o DESY, Hamburg Outstation, Hamburg, Germany
Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, Borstel, Germany, kbranden{at}fz-borstel.de
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA, Laboratories of Microbial Pathogenesis, Department of Veterans Affairs Medical Center, Atlanta, Georgia, USA
Meningococcal endotoxin is the major contributor to the pathogenesis of fulminant sepsis and meningitis of meningococcal disease and is a potent activator of the MyD88-dependent and MyD88-independent pathways via the MD-2/TLR4 receptor. To understand better the biological properties of meningococcal endotoxin that initiates these events, the physicochemical structure of Neisseria meningitidis lipopoly(oligo)saccharide (LOS) of the serogroup B wild-type strain NMB (NeuNAc-Galβ-GlcNAc-Galβ-Glcβ-Hep 2(GlcNAc,Glc
Key Words: Neisseria meningitidis • lipid A • 2-keto-3-deoxyoctonate (Kdo) • TLR4 • physicochemistry of endotoxins
Journal of Endotoxin Research, Vol. 13, No. 6,
343-357 (2007) |
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)PEA-Kdo2-lipid A, 1,4'-bisphosphorylated ± PEA, PEtN) and the genetically-defined mutants (gmhB, Kdo2 -lipid A; kdtA, meningococcal lipid A; gmhB—lpxL1, Kdo2penta-acylated lipid A and NMB—lpx1, penta-acylated meningococcal LOS) were assessed in relation to bioactivity. Confirming previous work, Kdo2-lipid A was the minimal structure required for optimal activation of the MD-2/TLR4 pathway of human macrophages. Meningococcal lipid A alone was a very weak agonist in stimulating human macrophages, even at high doses. Penta-acylated LOS structures demonstrated a moderate reduction in TLR4/MyD88-dependent signaling and a dramatic decrease in TLR4-TRIF-dependent signaling. For a better understanding of these results, we have performed an analysis of physicochemical parameters of the LOS structures such as the gel-to-liquid crystalline phase transition of the acyl chains, the inclination angle of the diglucosamine backbone with respect to the membrane surface, and the aggregate structure, and have found a very significant correlation of these parameters with biological activities extending our concept of endotoxicity.