Lipid A's structure mediates Neisseria gonorrhoeae fitness during experimental infection of mice and men

Abstract

Phosphoethanolamine (PEA) on Neisseria gonorrhoeae lipid A influences gonococcal inflammatory signaling and susceptibility to innate host defenses in in vitro models. Here, we evaluated the role of PEA-decorated gonococcal lipid A in competitive infections in female mice and in male volunteers. We inoculated mice and men with mixtures of wild-type N. gonorrhoeae and an isogenic mutant that lacks the PEA transferase, LptA. LptA production conferred a marked survival advantage for wild-type gonococci in the murine female genital tract and in the human male urethra. Our studies translate results from test tube to animal model and into the human host and demonstrate the utility of the mouse model for studies of virulence factors of the human-specific pathogen N. gonorrhoeae that interact with non-host-restricted elements of innate immunity. These results validate the use of gonococcal LptA as a potential target for development of novel immunoprophylactic strategies or antimicrobial treatments.

Importance: Gonorrhea is one of the most common bacterial sexually transmitted infections, and increasing antibiotic resistance threatens the use of currently available antimicrobial therapies. In this work, encompassing in vitro studies and in vivo studies of animal and human models of experimental genital tract infection, we document the importance of lipid A's structure, mediated by a single bacterial enzyme, LptA, in enhancing the fitness of Neisseria gonorrhoeae. The results of these studies suggest that novel agents targeting LptA may offer urgently needed prevention or treatment strategies for gonorrhea.

FIG 1

PEA decoration of N. gonorrhoeae lipid A confers a competitive advantage during genital tract infection. The competitive index (CI) was equal to [FA1090 ΔlptA or C′FA1090 ΔlptA/FA1090 (output)]/[FA1090 ΔlptA or C′FA1090 ΔlptA/FA1090 (input)]. (A) Competitive infections in female BALB/c mice (n = 7) with FA1090 ΔlptA and FA1090; (B) female BALB/c mice (n = 7) with C′FA1090 ΔlptA and FA1090; (C) male volunteers (n = 6) with FA1090 ΔlptA and FA1090. Note the different y axis scale in panel C, imposed by the limit of detection of 100-fold-decreased fitness in experimental human infections. (A and C) A CI of <1 indicates that the mutant is less fit than the wild type. Solid circles indicate mice from which both wild-type N. gonorrhoeae FA1090 and FA1090 ΔlptA were recovered (A) and both wild-type N. gonorrhoeae FA1090 and C′FA1090 ΔlptA/FA1090 were recovered (B). Open circles indicate infected mice or men from whom only wild-type N. gonorrhoeae FA1090 was recovered (A and C) or only C′FA1090 ΔlptA was recovered (B). Horizontal bars indicate geometric mean CIs.