title: Neisserial lipooligosaccharide is a target for complement component C4b. Inner core phosphoethanolamine residues define C4b linkage specificity.
abstract: We identified Neisseria meningitidis lipooligosaccharide (LOS) as an acceptor for complement component C4b (C4b). Phosphoethanolamine (PEA) residues on the second heptose (HepII) residue in the LOS core structure formed amide linkages with C4b. PEA at the 6-position of HepII (6-PEA) was more efficient than 3-PEA in binding C4b. Strains bearing 6-PEA bound more C4b than strains with 3-PEA and were more susceptible to complement-mediated killing in serum bactericidal assays. Deleting 3-PEA from a strain that expressed both 3- and 6-PEA simultaneously on HepII did not decrease C4b binding. Glycose chain extension of the first heptose residue (HepI) influenced the nature of the C4b-LOS linkage. Predominantly ester C4b-LOS bonds were seen when lacto-N-neotetraose formed the terminus of the glycose chain extension of HepI with 3-PEA on HepII in the LOS core. Related LOS species with more truncated chain extensions from HepI bound C4b via amide linkages to 3-PEA on HepII. However, 6-PEA in the LOS core bound C4b even when the glycose chain from HepI bore lacto-N-neotetraose at the terminus. The C4A isoform exclusively formed amide linkages, whereas C4B bound meningococci preferentially via ester linkages. These data may serve to explain the preponderance of 3-PEA-bearing meningococci among clinical isolates, because 6-PEA enhances C4b binding that may facilitate clearance of 6-PEA-bearing strains resulting from enhanced serum killing by the classical pathway of complement.
authors.affiliation: Section of Infectious Diseases, Evans Biomedical Research Center, Boston University Medical Center, Boston, Massachusetts 02118, USA. sram@bu.edu
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cox
authors.forename: J Claire
authors.initials: JC
authors.lastname: Wright
authors.forename: Ulrich
authors.initials: U
authors.lastname: Vogel
authors.forename: Silke
authors.initials: S
authors.lastname: Getzlaff
authors.forename: Ryan
authors.initials: R
authors.lastname: Boden
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Plested
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
authors.forename: Sunita
authors.initials: S
authors.lastname: Gulati
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Stein
authors.forename: James C
authors.initials: JC
authors.lastname: Richards
authors.forename: E Richard
authors.initials: ER
authors.lastname: Moxon
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rice
mesh_terms: D000577:Amides; D015935:Complement C4b / Q000276:immunology / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004983:Ethanolamines; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008970:Molecular Weight; D009345:Neisseria meningitidis / Q000737:chemistry* / Q000276:immunology; D011485:Protein Binding
chemical_list: D000577:Amides; D004983:Ethanolamines; D008070:Lipopolysaccharides; C023023:lipid-linked oligosaccharides; C005448:phosphorylethanolamine; D015935:Complement C4b