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Neisseria gonorrhoeae survival during primary human cervical epithelial cell infection requires nitric oxide and is augmented by progesterone.

ABSTRACT: Neisseria gonorrhoeae is an obligate human pathogen that causes gonorrhea. We have shown previously that complement receptor 3 and Akt kinase play important roles in mediating cervical infection. At present, there are limited data to indicate how hormonally induced changes to the mucosal epithelia of the female genital tract mediate the course of gonococcal disease. Hence, I have expanded upon previous work to investigate the interaction of gonococci with primary human cervical epithelial (pex) cells under the variable estrogen and progesterone concentrations likely to be encountered in vivo throughout the female menstrual cycle. My data indicated that the ability of gonococci to survive and to replicate within pex cells was increased under progesterone-predominant conditions. Using bacterial survival, immunological, and kinase assays, I show that progesterone functioned in an additive manner with gonococcal phospholipase D to augment Akt kinase activity. This, in turn, resulted in a parallel increase in nitric oxide synthase expression. Nitric oxide production by pex cells was dependent upon Akt activity and was increased under progesterone-predominant conditions. Whereas both inducible and endothelial nitric oxide synthase contributed to nitric oxide production, only inducible nitric oxide synthase activity promoted gonococcal survival within pex cells. Collectively, these data provide the first clues as to how steroid hormones potentially modulate the course of gonococcal disease in women. In addition, these data demonstrate that host-derived nitric oxide likely is not protective against gonococci, in vivo; rather, nitric oxide may be required to sustain cervical bacterial disease.

SUBMITTER: Edwards JL

PROVIDER: S-EPMC2825954 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Neisseria gonorrhoeae is a significant threat to global health for which a vaccine and novel treatment options are urgently needed. Glycans expressed by human cells are commonly targeted by pathogens to facilitate interactions with the host, and thus characterization of these interactions can aid identification of bacterial receptors that can be exploited as vaccine and/or drug targets. Using glycan array analysis, we identified 247 specific interactions between N. gonorrhoeae and glycans representative of those found on human cells. Interactions included those with mannosylated, fucosylated, and sialylated glycans, glycosaminoglycans (GAGs), and glycans terminating with galactose (Gal), N-acetylgalactosamine (GalNAc), and N-acetylglucosamine (GlcNAc). By investigating the kinetics of interactions with selected glycans, we demonstrate that whole-cell N. gonorrhoeae has a high affinity for mannosylated glycans (dissociation constant [KD ], 0.14 to 0.59??M), which are expressed on the surface of cervical and urethral epithelial cells. Using chromatography coupled with mass spectrometric (MS) analysis, we identified potential mannose-binding proteins in N. gonorrhoeae Pretreatment of cells with mannose-specific lectin (concanavalin A) or free mannose competitor (?-methyl-d-mannopyranoside) substantially reduced gonococcal adherence to epithelial cells. This suggests that N. gonorrhoeae targets mannosyl glycans to facilitate adherence to host cells and that mannosides or similar compounds have the potential to be used as a novel treatment option for N. gonorrhoeae IMPORTANCE Multidrug-resistant strains of Neisseria gonorrhoeae are emerging worldwide, and novel treatment and prevention strategies are needed. Glycans are ubiquitously expressed by all human cells and can be specifically targeted by pathogens to facilitate association with host cells. Here we identify and characterize the N. gonorrhoeae host-glycan binding profile (glycointeractome), which revealed numerous interactions, including high-affinity binding to mannosyl glycans. We identify gonococcal potential mannose-binding proteins and show that N. gonorrhoeae uses mannosyl glycans expressed on the surface of cervical and urethral epithelia to facilitate adherence. Furthermore, a mannose-binding lectin or a mannoside compound was able to reduce this adherence. By characterizing the glycointeractome of N. gonorrhoeae, we were able to elucidate a novel mechanism used by this important pathogen to interact with human cells, and this interaction could be exploited to develop novel therapeutics to treat antibiotic-resistant gonorrhea.

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Neisseria gonorrhoeae survival during primary human cervical epithelial cell infection requires nitric oxide and is augmented by progesterone.

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