MolBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history

Mykhaylo Usyk,Christopher C Sollecito,Nicolas F Schlecht,Howard D Strickler,Null Author_Id ,Carolina Porras,Anne Nucci‐Sack ,Ángela Díaz ,Sarah Pickering,Lígia A Pinto ,Ana Gradíssimo ,Mahboobeh Safaeian,Shankar Viswanathan,Rolando Herrero,Lashanda R Williams ,Robert D Burk

doi:10.1038/s41467-021-27628-3

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.

Highlights

Bacterial vaginosis (BV) is a highly prevalent condition that is associated with adverse health outcomes
The fungal community clustering showed no significant association with binary BV diagnosis, some clustering was observed for both the Nugent (p-value = 0.18) and Amsel BVpositive samples (p-value = 0.22)
To identify specific taxa associated with BV using ANCOM, we focused on the samples with concordant results for BV by Amsel and Nugent criteria (Supplementary Table 1); 52 differentially abundant genera were identified (FDR < 0.05, Fig. 1E), with Lactobacillus being the dominant genus elevated in BV-negative women and a mixture of anaerobic Gram-negative bacteria such as Gardnerella elevated in BV-positive, as expected[39,40,41]

Summary

Introduction

Bacterial vaginosis (BV) is a highly prevalent condition that is associated with adverse health outcomes. Clinical BV is primarily diagnosed using Amsel criteria[22], which requires the presence of three out of four signs or symptoms: (1) homogeneous, thin, white discharge that smoothly coats the vaginal walls; (2) clue cells in a wet mount; (3) pH of vaginal fluid >4.5; and (4) a fishy odor from the vaginal discharge before or after addition of 10% KOH (i.e., whiff test). An alternative to Amsel’s criteria is the Nugent score that creates a composite score based on counts of key bacteria morphologically identified on a Gram stain (i.e., Lactobacillus, Gardnerella, and curved Gram-negative rods)[24] This method is more sensitive than the Amsel criteria[24,25,26], it has been shown to suffer from interobserver variability[27] and its use has primarily been limited to research settings due to the amount of time, expertise, and costs required to perform the test[28]. It is important to identify the source of this variability since the pathogenic effects of BV appear to be associated with local inflammation[14,32,34,35,36]

Methods

Results

Conclusion