The mucosal immune responses of the human cervix are modulated by Neisseria gonorrhoeae

Abstract

Abstract The cervix is the gate to the upper female reproductive tract (FRT), and the mucosal surface is the first line of defense against pathogens. The sexually transmitted pathogen Neisseria gonorrhoeae (GC) infects from the lower tract and does not induce inflammation until GC ascends through the cervix to the upper FRT, suggesting immune evasion. We examined local immune responses in the human cervix to GC infection during the first 24 hours using a human tissue explant model. GC inoculation increased the secretion of the pro-inflammatory cytokines IL-1β, TNF-α, and TNF-β, the anti-inflammatory cytokines IL-10 and LIF, and the chemokines IL-8, CXCL1, CXCL2, and CCL3. GC expressing opacity-associated protein Opa 52(binds to CEACAM) enhanced anti-inflammatory cytokines production. The elevated cytokine production was concurrent with increased nuclear staining of NF-κB p65. RNAseq analysis found increases in mRNA levels of cytokines and NF-κB pathway genes in GC-inoculated cervical tissues, compared to no GC controls. Inhibiting NF-κB activation by Bay reduced GC-induced secretion of pro-inflammatory but not anti-inflammatory cytokines. While macrophages and T-cells were abundant in the human cervix, colonization of GC expressing Opa 52did not recruit the immune cells, despite the induction of chemokines and cytokines. However, colonization of Opa-deleted GC recruited macrophages to the subepithelium of the cervical transformational zone and increased the number of CD3+ T-cells contacting Langerhans cells in the ectocervical epithelium. Together these results suggest that GC infection modulates the balance of the cervical cytokine environment towards anti-inflammatory to suppress local inflammatory responses. Supported by grants from NIH RO1 AI141894 and RO1 AI123340