Editors' ChoiceHost-Pathogen Interactions

Intimate encounters with Neisseria gonorrhoeae

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Science Signaling  09 Jun 2020:
Vol. 13, Issue 635, eabd1493
DOI: 10.1126/scisignal.abd1493

Adhesion to host cells localizes gonococcal NO production to suppress epithelial exfoliation.

Physiological exfoliation maintains epithelial homeostasis and protects against colonization by pathogens. Neisseria gonorrhoeae suppresses exfoliation by stimulating epithelial cells to produce endoglin (ENG, also known as CD105), a matrix-binding protein that is normally produced by endothelial cells. This requires N. gonorrhoeae adhesion proteins, such as those of the Opa family, that bind to host cell adhesion molecules of the CEACAM family. Muenzner and Hauck found that although N. gonorrhoeae–induced ENG production in cultured human 293T cells required the engagement of CEACAM molecules, it did not require CEACAM downstream signaling. Instead, it required nitric oxide (NO) production by the bacteria and soluble guanylate cyclase (sGC) and the canonical protein kinase G (PKG) signaling pathway in host cells, which culminated in the activation of ENG expression by cAMP response element–binding protein (CREB). Purified AniA, a N. gonorrhoeae outer membrane enzyme that produces NO, suppressed epithelial exfoliation in vitro. In a model of N. gonorrhoeae vaginal infection in transgenic mice expressing a human CEACAM, application of purified AniA enabled mutant N. gonorrhoeae that could not engage CEACAMs to suppress exfoliation and establish infection, but a mutated form of AniA that cannot generate NO did not. Similarly, pharmacological activation of sGC enabled non–CEACAM-binding gonococci to suppress exfoliation and establish infection, and pharmacological inhibition of sGC prevented Opa-producing gonococci from suppressing exfoliation and establishing infection. These findings imply that tight adhesion of N. gonorrhoeae to epithelial cells is required to concentrate bacterial NO production in close proximity to the host cell. This intimate association between bacteria and host cells may be involved in colonization by other pathogens that can bind to CEACAMs (see commentary by Dillard).

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