Gonorrhea remains a major global health concern and is typically confined to the urogenital tract; however, a subset of infections can progress to disseminated gonococcal infection (DGI), resulting in bacteremia and systemic disease. The microbial and host factors that enable Neisseria gonorrhoeae to transition from localized mucosal infection to bloodstream dissemination remain incompletely defined. We investigated whether phenotypic differences and their subsequent interactions with host cells may contribute to divergent clinical outcomes.
We analyzed matched pairs of N. gonorrhoeae isolates obtained from the genital tract and blood of patients who were diagnosed with DGI. These paired isolates were of the same multilocus sequence type. In vitro assays evaluated bacterial aggregation, interaction with epithelial cells, and capacity to transmigrate across polarized epithelial monolayers. Host transcriptomic analysis identified genes differentially expressed upon exposure to the blood and genital tract isolates from the same patient.
The disseminated blood isolates displayed markedly reduced self-aggregation but significantly enhanced transmigration across epithelial barriers, compared to their localized counterparts. While the localized genital tract isolates initially demonstrated limited transmigration, bacteria recovered after transmigration exhibited enhanced transmigrating capability, similar to those of disseminated isolates. Disseminated blood isolates recruited carcinoembryonic antigen–related cell adhesion molecules (CEACAMs) at the epithelial surface far less frequently than localized cervical isolates, indicating reduced expression or functional engagement of CEACAM-binding Opa variants. Transcriptionally, the blood isolate induced an innate antimicrobial immune response and modulated host response to immune signals. While the genital tract isolate modulated epithelial cell-cell interactions, tissue organization, and cross-talk between metabolic and inflammatory pathways, among others.
Collectively, these findings suggest that phase-variable downregulation of specific Opa proteins diminishes bacterial aggregation and epithelial receptor engagement, thereby facilitating traversal of epithelial barriers and systemic spread. Additionally, when the isolates interact with genital tract cells, they trigger different pathways that either facilitate their ability to function in that environment (cervical) or facilitate their evasion of the immune response so they can traverse further into the system (blood). This work suggests that phenotypic switching may be a key determinant of dissemination in gonococcal infection.