The Immune Landscape of Molecular Bacterial Vaginosis and HPV Natural History

Bacterial vaginosis (BV) is a highly prevalent condition that is associated with acquisition of sexually transmitted infections and adverse reproductive outcomes. It has been proposed that BV’s role as a pathogenic condition is mediated via bacteria-induced local inflammation. However, the complex interplay between vaginal microbes and host immune factors has yet to be clearly elucidated. We demonstrate that 16S rRNA amplicon sequencing and a novel pipeline can be used to generate a molecular Nugent BV score (molBV) corresponding to the Nugent score 0 - 10. This algorithm is independent of the region of 16S rRNA amplified, the sequencing platform and source population. We further identify two local immune cytokine patterns associated with this molecular Nugent score (q-values<0.001). The main immune response is represented by an elevated IL-1β/IP-10 ratio, whereas a second pattern consists of an increased TNF-α/MIP-1β ratio. To evaluate the biological significance of molBV-BV and the local immune response, we show that clearance of high-risk HPV (HR-HPV) infections (HZ=1.86, 95% CI: 1.19-2.9) was associated with immune profiles, but not molBV-BV when both were considered in the model. In contrast, the TNF-α/MIP-1β signature was associated with progression of incident infections to CIN2+ (OR = 2.81, 95% CI: 1.62-5.42), but not HR-HPV clearance. Thus, BV is a heterogeneous condition that activates different arms of the local immune response, which in turn are independent risk factors for HR-HPV clearance and progression.