molBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history
Mykhaylo Usyk, Nicolas F. Schlecht, Sarah Pickering, LaShanda Williams, Christopher C. Sollecito, Ana Gradíssimo, Carolina Porras, Mahboobeh Safaeian, Lígia A. Pinto, Rolando Herrero, Howard D. Strickler, V. Shankar, Anne Nucci‐Sack, Ángela Díaz, Costa Rica HPV Vaccine Trial (CVT) Group, Bernal Cortés, Paula González, Silvia E. Jiménez, Ana Cecilia Rodríguez, Allan Hildesheim, Aimée R. Kreimer, Douglas R. Lowy, Mark Schiffman, John T. Schiller, Mark E. Sherman, Sholom Wacholder, Troy J. Kemp, Mary Sidawy, Wim Quint, Leen‐Jan van Doorn, Linda Struijk, Joel M. Palefsky, Teresa M. Darragh, Mark H. Stoler, Robert D. Burk
Abstract
Bacterial vaginosis (BV) is a highly prevalent condition that is associated with adverse health outcomes. It has been proposed that BV's role as a pathogenic condition is mediated via bacteria-induced inflammation. However, the complex interplay between vaginal microbes and host immune factors has yet to be clearly elucidated. Here, we develop molBV, a 16 S rRNA gene amplicon-based classification pipeline that generates a molecular score and diagnoses BV with the same accuracy as the current gold standard method (i.e., Nugent score). Using 3 confirmatory cohorts we show that molBV is independent of the 16 S rRNA region and generalizable across populations. We use the score in a cohort without clinical BV states, but with measures of HPV infection history and immune markers, to reveal that BV-associated increases in the IL-1β/IP-10 cytokine ratio directly predicts clearance of incident high-risk HPV infection (HR = 1.86, 95% CI: 1.19-2.9). Furthermore, we identify an alternate inflammatory BV signature characterized by elevated TNF-α/MIP-1β ratio that is prospectively associated with progression of incident infections to CIN2 + (OR = 2.81, 95% CI: 1.62-5.42). Thus, BV is a heterogeneous condition that activates different arms of the immune response, which in turn are independent risk factors for HR-HPV clearance and progression. Clinical Trial registration number: The CVT trial has been registered under: NCT00128661.