Relationship between the Cervical Microbiome, HIV Status, and Precancerous Lesions.

Cameron Klein,John T West,Nirosh Aluthge,Kandali Samwel,Julius Mwaiselage,Daniela Gonzalez,Crispin Kahesa,Samodha Fernando,Charles Wood,Peter C Angeletti

doi:10.1128/mbio.02785-18

Cameron Klein, John T West + Show 8 more

Open Access

https://doi.org/10.1128/mbio.02785-18

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Abstract

Nearly all cervical cancers are causally associated with human papillomavirus (HPV). The burden of HPV-associated dysplasias in sub-Saharan Africa is influenced by HIV. To investigate the role of the bacterial microbiome in cervical dysplasia, cytobrush samples were collected directly from cervical lesions of 144 Tanzanian women. The V4 hypervariable region of the 16S rRNA gene was amplified and deep sequenced. Alpha diversity metrics (Chao1, PD whole tree, and operational taxonomic unit [OTU] estimates) displayed significantly higher bacterial richness in HIV-positive patients (P = 0.01) than in HIV-negative patients. In HIV-positive patients, there was higher bacterial richness in patients with high-grade squamous intraepithelial lesions (HSIL) (P = 0.13) than those without lesions. The most abundant OTUs associated with high-grade squamous intraepithelial lesions were Mycoplasmatales, Pseudomonadales, and Staphylococcus We suggest that a chronic mycoplasma infection of the cervix may contribute to HPV-dependent dysplasia by sustained inflammatory signals.IMPORTANCE HPV is known to be the causal agent in the majority of cervical cancers. However, the role of the cervical bacterial microbiome in cervical cancer is not clear. To investigate that possibility, we collected cervical cytobrush samples from 144 Tanzanian women and performed deep sequencing of bacterial 16S rRNA genes. We found that HIV-positive patients had greater bacterial richness (P = 0.01) than HIV-negative patients. We also observed that women with high-grade squamous intraepithelial lesions (HSIL) had greater cervical bacterial diversity than women with cytologically normal cervices. Data from our precise sampling of cervical lesions leads us to propose that Mycoplasma contributes to a cervical microbiome status that promotes HPV-related cervical lesions. These results suggest a greater influence of the bacterial microbiota on the outcome of HPV infection than previously thought.

Highlights

Most cervical cancers are causally associated with human papillomavirus (HPV)
Chronic inflammation of the cervix, which is a result of cervicovaginal pathogens, leads to conditions like pelvic inflammatory disease (PID) and bacterial vaginosis (BV), both of which are associated with persistent HPV infection and cervical cancer [18, 19]
Given that cervical cancer rates are expected to rise in sub-Saharan Africa as the HIV-positive population receives life-extending antiretroviral therapy (ART), it is even more important to understand the risk factors associated with the cervical microbiome

Summary

Introduction

Most cervical cancers are causally associated with human papillomavirus (HPV). The burden of HPV-associated dysplasias in sub-Saharan Africa is influenced by HIV. Data from our precise sampling of cervical lesions leads us to propose that Mycoplasma contributes to a cervical microbiome status that promotes HPV-related cervical lesions These results suggest a greater influence of the bacterial microbiota on the outcome of HPV infection than previously thought. Chronic inflammation of the cervix (cervicitis), which is a result of cervicovaginal pathogens, leads to conditions like pelvic inflammatory disease (PID) and bacterial vaginosis (BV), both of which are associated with persistent HPV infection and cervical cancer [18, 19] Both PID and BV are more prevalent in sub-Saharan Africa and in HIV-positive populations [20,21,22]. Cervical cytology is graded by pap smear screening for nuclear abnormalities according to the Bethesda guidelines

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