Distinct Cervicovaginal Cytokine Signatures Associated with Reproductive Tract Infections and Vaginal Dysbiosis Across Diverse Settings

BackgroundReproductive tract infections (RTIs) and bacterial vaginosis (BV) are major causes of genital inflammation and reproductive morbidity, yet often remain undetected under syndromic management. We evaluated cervicovaginal cytokine signatures associated with RTIs and vaginal dysbiosis in women from South Africa, Madagascar, and Zimbabwe. MethodsVaginal swabs from 676 non-pregnant, sexually-active women (18-35 years) were tested for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV), Mycoplasma genitalium (MG), Candida spp., and BV by PCR and Nugent scoring. Cervicovaginal IL-1, IL-1{beta}, and IP-10 concentrations were measured by ELISA, and associations with RTIs and vaginal dysbiosis were assessed using multivariable regression and population attribution fraction analyses. ResultsBV (Nugent 7-10) was the most prevalent (50.4%) and dominant contributor to elevated IL-1 and IL-1{beta}, accounting for >60% of women with high cytokine levels. Intermediate vaginal microbiota (Nugent 4-6) showed similar inflammatory profiles and, with BV, was associated with reduced IP-10. NG was independently associated with elevated IL-1 and IL-1{beta}, CT with elevated IL-1{beta} and IP-10, TV with elevated IP-10, Candida spp. with elevations in all cytokines, while MG showed no independent associations. Most RTIs and vaginal dysbiosis were asymptomatic, with similar inflammatory profiles regardless of symptoms. Despite variation in baseline cytokine concentrations, infection-associated inflammatory signatures were consistent across countries. ConclusionsRTIs and vaginal dysbiosis elicited consistent inflammatory signatures across countries, with BV and intermediate microbiota driving much of the inflammatory burden. Their frequent occurrence in asymptomatic women highlights the potential of host-response biomarkers to identify otherwise undetected genital inflammation. Lay summaryReproductive tract infections and bacterial vaginosis (BV; a common condition in which the normal protective bacteria in the vagina are replaced by a mix of other bacteria) are major causes of poor reproductive health, but many women have no symptoms and remain undiagnosed. In this study, we measured inflammatory proteins in vaginal samples from 676 women in South Africa, Madagascar, and Zimbabwe and examined how these markers were associated with infections and changes in the vaginal microbiota. We found that BV was the strongest driver of genital inflammation and that women with intermediate vaginal microbiota, often considered a transitional microbial state, showed similar inflammatory profiles. Different infections were associated with distinct inflammatory patterns, but many women with substantial inflammation had no symptoms. Importantly, these inflammatory responses were broadly similar across all three countries. Together, these findings highlight important limitations of symptom-based diagnosis and support the development of host-response diagnostics that can identify by reproductive tract infections and vaginal dysbiosis, including in women who would otherwise remain undiagnosed.