Phosphoethanolamine substitution of lipid A and resistance of Neisseria gonorrhoeae to cationic antimicrobial peptides and complement-mediated killing by normal human serum

Infect Immun. 2009 Mar;77(3):1112-20. doi: 10.1128/IAI.01280-08. Epub 2008 Dec 29.

Abstract

The capacity of Neisseria gonorrhoeae to cause disseminated gonococcal infection requires that such strains resist the bactericidal action of normal human serum. The bactericidal action of normal human serum against N. gonorrhoeae is mediated by the classical complement pathway through an antibody-dependent mechanism. The mechanism(s) by which certain strains of gonococci resist normal human serum is not fully understood, but alterations in lipooligosaccharide structure can affect such resistance. During an investigation of the biological significance of phosphoethanolamine extensions from lipooligosaccharide, we found that phosphoethanolamine substitutions from the heptose II group of the lipooligosaccharide beta-chain did not impact levels of gonococcal (strain FA19) resistance to normal human serum or polymyxin B. However, loss of phosphoethanolamine substitution from the lipid A component of lipooligosaccharide, due to insertional inactivation of lptA, resulted in increased gonococcal susceptibility to polymyxin B, as reported previously for Neisseria meningitidis. In contrast to previous reports with N. meningitidis, loss of phosphoethanolamine attached to lipid A rendered strain FA19 susceptible to complement killing. Serum killing of the lptA mutant occurred through the classical complement pathway. Both serum and polymyxin B resistance as well as phosphoethanolamine decoration of lipid A were restored in the lptA-null mutant by complementation with wild-type lptA. Our results support a role for lipid A phosphoethanolamine substitutions in resistance of this strict human pathogen to innate host defenses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Antimicrobial Cationic Peptides / immunology*
  • Antimicrobial Cationic Peptides / pharmacology
  • Complement System Proteins / immunology*
  • Drug Resistance, Microbial / genetics*
  • Drug Resistance, Microbial / immunology
  • Ethanolamines / chemistry
  • Ethanolamines / immunology*
  • Gonorrhea / immunology
  • Humans
  • Lipid A / chemistry*
  • Lipid A / genetics
  • Lipid A / immunology
  • Neisseria gonorrhoeae / genetics
  • Neisseria gonorrhoeae / immunology*
  • Neisseria gonorrhoeae / pathogenicity
  • Polymyxin B / pharmacology
  • Serum / immunology
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Ethanolamines
  • Lipid A
  • phosphorylethanolamine
  • Complement System Proteins
  • Polymyxin B