IAI Accepts, published online ahead of print on 29 December 2008

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Infect. Immun. doi:10.1128/IAI.01280-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Phosphoethanolamine Substitution of Lipid A and Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides and Complement-Mediated Killing by Normal Human Serum

Lisa A. Lewis, Biswa Choudhury, Jacqueline T. Balthazar, Larry E. Martin, Sanjay Ram, Peter A. Rice, David S. Stephens, Russell Carlson, and William M. Shafer^*

Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA; Department of Biochemistry, and Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia; Laboratories of Bacterial Pathogenesis, Medical Research Service, Veterans Affairs Medical Center (Atlanta), Decatur, GA 30033; and Departments of Microbiology and Immunology and Medicine, Emory University School of Medicine, Atlanta, GA 30322

^* To whom correspondence should be addressed. Email: wshafer{at}emory.edu.

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 -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 N. 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 the wild type lptA. Our results support a role for lipid A phosphoethanolamine substitutions in resistance of this strict human pathogen to innate host defenses.