title: Physicochemical characterization and biological activity of lipooligosaccharides and lipid A from Neisseria meningitidis.
abstract: 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-Gal beta-GlcNAc-Gal beta-Glc beta-Hep2(GlcNAc,Glc alpha)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, Kdo2lipid 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.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30033, USA. szughai@emory.edu
authors.forename: Susu M
authors.initials: SM
authors.lastname: Zughaier
authors.forename: Buko
authors.initials: B
authors.lastname: Lindner
authors.forename: Jörg
authors.initials: J
authors.lastname: Howe
authors.forename: Patrick
authors.initials: P
authors.lastname: Garidel
authors.forename: Michel H J
authors.initials: MH
authors.lastname: Koch
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
authors.forename: David S
authors.initials: DS
authors.lastname: Stephens
mesh_terms: D002240:Carbohydrate Sequence; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D008050:Lipid A / Q000737:chemistry / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D009345:Neisseria meningitidis / Q000378:metabolism*; D044367:Phase Transition; D010743:Phospholipids / Q000737:chemistry; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D008050:Lipid A; D008070:Lipopolysaccharides; D010743:Phospholipids; C023023:lipid-linked oligosaccharides