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

Résumé

Background Reproductive tract infections (RTIs) and bacterial vaginosis (BV) cause significant reproductive morbidity but often remain undetected. We evaluated cervicovaginal cytokine signatures associated with RTIs and vaginal dysbiosis in women from South Africa, Madagascar, and Zimbabwe. Methods Vaginal swabs from 676 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. IL-1α, IL-1β, and IP-10 were measured by ELISA; associations were assessed using multivariable regression and population attributable fractions. Results BV prevalence was 50.4% (337/668), followed by CT (15.0%), TV (11.8%), NG (5.7%), MG (4.5%), and Candida spp. (6.8%). BV dominated elevated IL-1α/IL-1β, accounting for >60% of high cytokine responses. Intermediate microbiota (Nugent 4–6) showed similar inflammatory profiles and, with BV, reduced IP-10. Independently, NG was associated with elevated IL-1α/IL-1β; CT with elevated IL-1β/IP-10; TV with elevated IP-10; Candida spp. with all cytokines; MG showed no association. Most infections were asymptomatic, eliciting similar inflammatory profiles to symptomatic cases. Pathogen-specific inflammatory signatures were consistent across countries. Conclusions RTIs and dysbiosis elicited consistent inflammatory signatures across countries. Their high prevalence in asymptomatic women highlights the potential of host-response biomarkers to identify undetected genital inflammation (ClinicalTrials.gov: NCT05723484 ). Lay summary Reproductive 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.

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