Neisseria gonorrhoeae Blocks Epithelial Exfoliation by Nitric-Oxide-Mediated Metabolic Cross Talk to Promote Colonization in Mice

Abstract

Several pathogens suppress exfoliation, a key defense of epithelia against microbial colonization. Common among these pathogens, exemplified by Neisseria gonorrhoeae, is their ability to bind carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). Gonococcal CEACAM engagement triggers the expression of CD105, which is necessary to block epithelial exfoliation, whereas homotypic CEACAM-CEACAM interactions or antibody-mediated CEACAM clustering does not lead to CD105 expression. Here, we show that CEACAM-associated bacteria release nitric oxide (NO) during anaerobic respiration, and membrane-permeable NO initiates a eukaryotic signaling pathway involving soluble guanylate cyclase (sGC), protein kinase G, and the transcription factor CREB to upregulate CD105 expression. A murine vaginal infection model with N. gonorrhoeae reveals this metabolic cross communication allows bacterial suppression of epithelial exfoliation to facilitate mucosal colonization. Disrupting NO-initiated responses in host cells re-establishes epithelial exfoliation and inhibits mouse genital tract colonization by N. gonorrhoeae, suggesting a host-directed approach to prevent bacterial infections.