Background: Most Neisseria gonorrhoeae infections in women are asymptomatic or subclinical. Neither asymptomatic nor symptomatic infections elicit protective immunity against subsequent infection. How gonococci maintain colonization without triggering immune responses in the human cervix remains unknown.
Aims and Methods: Using a human cervical tissue explant model, combined with Luminex, immunofluorescence microscopy, and spatial transcriptomics, we examined the earliest immune signals to gonococcal infection, the local cytokine response.
Results: Ectocervical epithelial cells produce the IL-1 receptor antagonist IL-1RA at a much higher level than the inflammatory cytokines IL-1α and IL-1β combined. Gonococcal colonization further enhances IL-1RA production, which depends on gonococcal expression of opacity-associated proteins that bind to human CEACAMs. IL-1RA production is required for gonococcal colonization by preventing bacteria-associated epithelial cells from shedding. Macrophages adjacent to the ectocervical epithelium express tissue-repair transcriptomic signature genes and IL-1RA, and they exhibit no response to gonococcal colonization. In contrast, macrophages deep within the ectocervical tissue increase expression of inflammatory and multifunctional cytokines, as well as M1- or M2-signature genes, in response to gonococcal infection.
Conclusion: Ectocervical epithelial cells and subepithelial tissue repair macrophages create an IL-1RA-dominated anti-inflammatory environment, which is further boosted by gonococcal colonization in a CEACAM-dependent manner. This anti-inflammatory environment enables gonococcal asymptomatic colonization of the human cervix.