Cervicovaginal microbiome and natural history of HPV in a longitudinal study

Study information

Reviewed Marked as Reviewed by Fatima Zohra on 2021/02/09

study design

time series / longitudinal observational

Citation

PMID PubMed identifier for scientific articles.

32214382

DOI Digital object identifier for electronic documents.

10.1371/journal.ppat.1008376

URI

Authors

Usyk M, Zolnik CP, Castle PE, Porras C, Herrero R, Gradissimo A, Gonzalez P, Safaeian M, Schiffman M, Burk RD

Journal

PLoS pathogens

Year

2020

BACKGROUND: Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections. However, only a small percentage of high-risk (HR) HPV infections progress to cervical precancer and cancer. In this study, we investigated the role of the cervicovaginal microbiome (CVM) in the natural history of HR-HPV. METHODS: This study was nested within the placebo arm of the Costa Rica HPV Vaccine Trial that included women aged 18-25 years of age. Cervical samples from two visits of women with an incident HR-HPV infection (n = 273 women) were used to evaluate the prospective role of the CVM on the natural history of HR-HPV. We focus specifically on infection clearance, persistence, and progression to cervical intraepithelial neoplasia grade 2 and 3 (CIN2+). The CVM was characterized by amplification and sequencing the bacterial 16S V4 rRNA gene region and the fungal ITS1 region using an Illumina MiSeq platform. OTU clustering was performed using QIIME2. Functional groups were imputed using PICRUSt and statistical analyses were performed using R. RESULTS: At Visit 1 (V1) abundance of Lactobacillus iners was associated with clearance of incident HR-HPV infections (Linear Discriminant Analysis (LDA)>4.0), whereas V1 Gardnerella was the dominant biomarker for HR-HPV progression (LDA>4.0). At visit 2 (V2), increased microbial Shannon diversity was significantly associated with progression to CIN2+ (p = 0.027). Multivariate mediation analysis revealed that the positive association of V1 Gardnerella with CIN2+ progression was due to the increased cervicovaginal diversity at V2 (p = 0.040). A full multivariate model of key components of the CVM showed significant protective effects via V1 genus Lactobacillus, OR = 0.41 (0.22-0.79), V1 fungal diversity, OR = 0.90 (0.82-1.00) and V1 functional Cell Motility pathway, OR = 0.75 (0.62-0.92), whereas V2 bacterial diversity, OR = 1.19 (1.03-1.38) was shown to be predictive of progression to CIN2+. CONCLUSION: This study demonstrates that features of the cervicovaginal microbiome are associated with HR-HPV progression in a prospective longitudinal cohort. The analyses indicated that the association of Gardnerella and progression to CIN2+ may actually be mediated by subsequent elevation of microbial diversity. Identified features of the microbiome associated with HR-HPV progression may be targets for therapeutic manipulation to prevent CIN2+. TRIAL REGISTRATION: ClinicalTrials.gov NCT00128661.

Experiment 1

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Reviewed Marked as Reviewed by Fatima Zohra on 2021/02/09

Curated date: 2021/01/10

Curator: WikiWorks

Revision editor(s): WikiWorks, Victoria

Subjects

Location of subjects: Costa Rica

Host species Species from which microbiome was sampled. Contact us to have more species added.: Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Uterine cervixUterine cervix

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: human papilloma virus infectionhuman papilloma virus infection

Group 0 name Corresponds to the control (unexposed) group for case-control studies: HPV (clearance)

Group 1 name Corresponds to the case (exposed) group for case-control studies: Visit 1 HPV (progression)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: HPV progression to CIN2+ lesion diagnosis

Group 0 sample size Number of subjects in the control (unexposed) group: 70

Group 1 sample size Number of subjects in the case (exposed) group: 33

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V4

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: LEfSe

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: No

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool: 2

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: unchanged

Signature 1

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Reviewed Marked as Reviewed by Fatima Zohra on 2021/02/09

Curated date: 2021/01/10

Curator: Cynthia Anderson

Revision editor(s): WikiWorks, Merit

Source: Figure 4

Description: Bacteria associated with progression to CIN2+ identified using LEfSe

Abundance in Group 1: increased abundance in Visit 1 HPV (progression)

NCBI	Quality Control	Links
Aerococcus christensenii
Anaerococcus prevotii
Bifidobacterium bifidum
Bifidobacterium longum subsp. longum
Blautia hansenii
Campylobacter canadensis
Campylobacter ureolyticus
Corynebacterium atypicum
Gardnerella vaginalis
Hallella bergensis
Methylobacillus flagellatus
Methylobacillus glycogenes
Neisseria gonorrhoeae
Peptoniphilus harei
Peptoniphilus indolicus
Porphyromonas bennonis
Prevotella melaninogenica
Prevotella veroralis
Schaalia meyeri
Schaalia odontolytica
Sphingomonas leidyi
Treponema pallidum
Veillonella montpellierensis