Variation of Neisseria gonorrhoeae Lipooligosaccharide Directs Dendritic Cell–Induced T Helper Responses

Abstract

Gonorrhea is one of the most prevalent sexually transmitted diseases in the world. A naturally occurring variation of the terminal carbohydrates on the lipooligosaccharide (LOS) molecule correlates with altered disease states. Here, we investigated the interaction of different stable gonoccocal LOS phenotypes with human dendritic cells and demonstrate that each variant targets a different set of receptors on the dendritic cell, including the C-type lectins MGL and DC-SIGN. Neisseria gonorrhoeae LOS phenotype C constitutes the first bacterial ligand to be described for the human C-type lectin receptor MGL. Both MGL and DC-SIGN are locally expressed at the male and female genital area, the primary site of N. gonorrhoeae infection. We show that targeting of different C-type lectins with the N. gonorrhoeae LOS variants results in alterations in dendritic cell cytokine secretion profiles and the induction of distinct adaptive CD4⁺ T helper responses. Whereas N. gonorrhoeae variant A with a terminal N-acetylglucosamine on its LOS was recognized by DC-SIGN and induced significantly more IL-10 production, phenotype C, carrying a terminal N-acetylgalactosamine, primarily interacted with MGL and skewed immunity towards the T helper 2 lineage. Together, our results indicate that N. gonorrhoeae LOS variation allows for selective manipulation of dendritic cell function, thereby shifting subsequent immune responses in favor of bacterial survival. Neisseria gonorrhoeae is a species of Gram-negative bacteria responsible for the sexually transmitted disease gonorrhea. Although effective antibiotic treatments are available, little is known about the host immune response to this pathogen. Here, we analyzed three well-characterized gonococcal variants that only differ in the outer sugar present on the lipooligosaccharide of the bacteria. We found that human dendritic cells use different receptors, including the C-type lectins MGL and DC-SIGN, to detect the three N. gonorrhoeae phenotypes. Dendritic cells carrying the MGL and DC-SIGN receptor were present in the human genital tissues, the site of gonoccocal invasion. DC activation with the gonococcal variants resulted in different cytokine secretion profiles and alterations in the subsequent adaptive T cell response. In particular, LOS containing a terminal N-acetylgalactosamine induced more T helper 2-type responses, which are unfavorable for clearing the bacteria. Our data provide new insights into the pathogenesis of N. gonorrhoeae and suggest that variation of lipooligosaccharide glycosylation enables to bacteria to selectively subvert host immune defense mechanisms.