Phosphoethanolamine residues on the lipid A moiety of Neisseria gonorrhoeae lipooligosaccharide modulate binding of complement inhibitors and resistance to complement killing.
Loss of phosphoethanolamine (PEA) from the lipid A of gonococcal strain FA19 results in increased sensitivity to killing by the classical pathway of complement. Here we demonstrate that loss of PEA from lipid A diminishes binding of the complement regulatory protein C4b binding protein (C4BP) to the FA19 porin B (PorB), providing a molecular basis to explain the susceptibility of an lptA null strain of FA19 to killing by normal human serum (NHS). Loss of PEA from lipid A in three additional gonococcal strains that expressed diverse PorB molecules also resulted in decreased C4BP binding, increased deposition of C4b, and increased susceptibility to killing by NHS. Complementation of lptA null strains with lptA restored C4BP binding, decreased C4b deposition, and increased resistance to killing by NHS. These effects of lipid A PEA on C4BP binding to gonococcal PorB and serum resistance were simulated when gonococcal PorB was expressed in a meningococcal background. Loss of PEA from lipid A also affected binding of the alternative pathway regulator factor H (fH) to PorB of some strains. For instance, PorB molecules of lptA null mutants of strains 252 and 1291 bound less fH than those of their parent strains when lipooligosaccharide (LOS) was sialylated, whereas PorB molecules of lptA null mutants of strains FA1090 and 273 retained the ability to bind fH when LOS was sialylated. These data indicate that replacement of lipid A with PEA alters binding of C4BP and fH to PorB and contributes to the ability of gonococci to resist complement-mediated killing.
Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA. lisa.lewis@umassmed.edu
Lisa A
LA
Lewis
William M
WM
Shafer
Tathagat
T
Dutta Ray
Sanjay
S
Ram
Peter A
PA
Rice
D015935:Complement C4b / Q000276:immunology / Q000378:metabolism; D050716:Complement C4b-Binding Protein / Q000276:immunology / Q000378:metabolism; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism*; D004983:Ethanolamines / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008050:Lipid A / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D009344:Neisseria gonorrhoeae / Q000276:immunology / Q000378:metabolism*; D018272:Porins / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology*; D044967:Serum / Q000276:immunology / Q000378:metabolism
D050716:Complement C4b-Binding Protein; D004983:Ethanolamines; D008050:Lipid A; D008070:Lipopolysaccharides; D018272:Porins; C023023:lipid-linked oligosaccharides; C057699:porin protein, Neisseria; C005448:phosphorylethanolamine; D015935:Complement C4b; D017242:Complement Factor H; D003165:Complement System Proteins