Phosphoethanolamine Residues on the Lipid A Moiety of Neisseria gonorrhoeae Lipooligosaccharide Modulate Binding of Complement Inhibitors and Resistance to Complement Killing

• Type of Material: Article
• Authors: Lisa A. Lewis, University of Massachusetts; William Shafer, Emory University; Tathagat Dutta Ray, New York University; Sanjay Ram, University of Massachusetts; Peter A. Rice, University of Massachusetts
• Language: English
• Date: 2013-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2013, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/IAI.00751-12
• Title of Journal or Parent Work: Infection and Immunity
• ISSN: 0019-9567
• Volume: 81
• Issue: 1
• Start Page: 33
• End Page: 42
• Grant/Funding Information: W.M.S. is the recipient of a Senior Research Career Scientist Award from the Department of Veterans Affairs Medical Research Service and is also supported in part by NIH grant U19 AI031496 (to P. F. Sparling, University of North Carolina-Chapel Hill).; This work was supported by NIH grants AI32725; and AI084048; to P.A.R. and AI054544 to S.R. and by a VA merit award to W.M.S.
• Keywords: EPITHELIAL-CELLS; Science & Technology; IMMUNOLOGY; C4B-BINDING PROTEIN; Infectious Diseases; BLOOD-CELLS; MOLECULAR CHARACTERIZATION; SIALIC-ACID; Life Sciences & Biomedicine; PATHOGENIC NEISSERIAE; INFECTIOUS DISEASES; NORMAL HUMAN-SERUM; LIPOPOLYSACCHARIDE ALTERATION; EPITOPE EXPRESSION; Immunology; FACTOR-H BINDING
• Research Categories: Health Sciences, Immunology; Biology, Virology; Biology, Microbiology

Abstract

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.