Phosphoethanolamine Decoration of Neisseria gonorrhoeae Lipid A Plays a Dual Immunostimulatory and Protective Role during Experimental Genital Tract Infection

• Type of Material: Article
• Authors: Mathanraj Packiam, Uniformed Services University of the Health Sciences; Roshan D. Yedery, Uniformed Services University of the Health Sciences; Afrin A. Begum, Uniformed Services University of the Health Sciences; Russell W. Carlson, University of Georgia; Jhuma Ganguly, University of Georgia; Gregory D. Sempowski, Duke University; Melissa S. Ventevogel, Duke University; William Shafer, Emory University; Ann E. Jerse, Uniformed Services University of the Health Sciences
• Language: English
• Date: 2014-06-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2014, American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/IAI.01504-14
• Title of Journal or Parent Work: Infection and Immunity
• ISSN: 0019-9567
• Volume: 82
• Issue: 6
• Start Page: 2170
• End Page: 2179
• Grant/Funding Information: Lipid A analysis was supported in part by a Department of Energy grant, DE-FG-02-93ER120097, to the Complex Carbohydrate Research Center (CCRC) (University of Georgia).; W.M.S. is the recipient of a Senior Research Career Scientist Award from the Department of Veterans Affairs, Medical Research Service.; This work was supported by NIH grants RO1 AI42053 (A.E.J.), U19 AI31496 (A.E.J., W.M.S., and G.D.S.), and R37 AI021150 (W.M.S.) and a VA Merit Award to W.M.S. from the Department of Veterans Affairs, Medical Research Service.
• Keywords: POLYMYXIN RESISTANCE; IN-VIVO FITNESS; IMMUNOLOGY; FEMALE REPRODUCTIVE-TRACT; MODULATION; GONOCOCCAL-INFECTION; EXPRESSION; INFECTIOUS DISEASES; ANTIMICROBIAL PEPTIDES; Life Sciences & Biomedicine; INFLAMMATION; EPITHELIAL-CELLS; Infectious Diseases; Science & Technology; MENINGITIDIS; Immunology
• Research Categories: Health Sciences, Immunology; Biology, Microbiology

Abstract

The induction of an intense inflammatory response by Neisseria gonorrhoeae and the persistence of this pathogen in the presence of innate effectors is a fascinating aspect of gonorrhea. Phosphoethanolamine (PEA) decoration of lipid A increases gonococcal resistance to complement-mediated bacteriolysis and cationic antimicrobial peptides (CAMPs), and recently we reported that wild-type N. gonorrhoeae strain FA1090 has a survival advantage relative to a PEA transferase A (lptA) mutant in the human urethral-challenge and murine lower genital tract infection models. Here we tested the immunostimulatory role of this lipid A modification. Purified lipooligosaccharide (LOS) containing lipid A devoid of the PEA modification and an lptA mutant of strain FA19 induced significantly lower levels of NF-κB in human embryonic kidney Toll-like receptor 4 (TLR4) cells and murine embryonic fibroblasts than wild-type LOS of the parent strain. Moreover, vaginal proinflammatory cytokine s and chemokines were not elevated in female mice infected with the isogenic lptA mutant, in contrast to mice infected with the wild-type and complemented lptA mutant bacteria. We also demonstrated that lptA mutant bacteria were more susceptible to human and murine cathelicidins due to increased binding by these peptides and that the differential induction of NF-κB by wild-type and unmodified lipid A was more pronounced in the presence of CAMPs. This work demonstrates that PEA decoration of lipid A plays both protective and immunostimulatory roles and that host-derived CAMPs may further reduce the capacity of PEA-deficient lipid A to interact with TLR4 during infection.