Monday, May 19, 2025
5/19/2025
Cellular mechanisms by which Neisseria gonorrhoeae infects the female reproductive tract - Project Summary Neisseria gonorrhoeae (GC) infect humans exclusively, primarily the genital tract, causing gonorrhea, which remains a public health crisis due to antibiotic resistance and no vaccines. GC infect both males and females, but women disproportionally suffer from severe complications. However, most female infections are asymptomatic. GC can colonize the vaginocervix asymptomatically for months, which delays treatments and allows infections to silently disseminate and ascend to the upper reproductive tract, leading to pelvic inflammatory disease and predisposing women to infertility and ectopic pregnancy. GC infection has been shown to induce mucosal cytokine secretion into vaginocervical secretions and in epithelial cell lines. However, the mechanism(s) used by GC to actively colonize the cervix without triggering immune detection remains unknown. Whether the local cytokine response plays a role in asymptomatic infection is also unclear. This proposal aims to determine the mechanisms by which GC manipulate the initial local cytokine response to enable asymptomatic colonization of the human cervix. Work supported by this grant has established an ex vivo GC cervical infection model mimicking GC in vivo infection, using human cervical tissue explants. This model gives us a unique opportunity to understand GC asymptomatic colonization at the cervix. Using this model, we have revealed the local IL-10 induction at the cervix as a mechanism for GC to inhibit local immune detection and promote GC colonization, which leads to our hypothesis: GC-epithelial cell interactions, dependent on GC surface structures, result in differential localized production of pro-inflammatory epithelial disrupting and anti-inflammatory epithelial repairing cytokines to interrupt the earliest signals of inflammation. To pursue this hypothesis, we will combine the cervical tissue explant model with isogenic GC strains, cutting- edge Luminex and tissue imaging technologies, and emerging spatial transcriptomic technologies. We will characterize the initial GC-induced cytokine production in the human cervix and the role of GC surface molecules in cytokine induction, determine how GC-induced cytokines promote asymptomatic infection in the cervix, and investigate how GC manipulate transcriptomic programs of cervical cells to induce cytokine production. The proposed studies will significantly advance our understanding of mechanisms underlying asymptomatic infections of GC and other sexually transmitted infections in women, filling critical knowledge gaps and enlightening novel ideas for designing preventatives and vaccines and understanding other challenging women’s health issues.
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