Systems Analysis Reveals Contraceptive-Induced Alteration of Cervicovaginal Gene Expression in a Randomized Trial

Christina Balle; Prachi M Gupta; Gregory K Tharp; Sydney A Nelson; Iyaloo N Konstantinus; Katie Lennard; Shameem Z Jaumdally; Anna-Ursula Happel; Shaun L Barnabas; Katherine Gill; Linda-Gail Bekker; Jo-Ann S Passmore; Heather B Jaspan; Steven E Bosinger

doi:10.3389/frph.2022.781687

Systems Analysis Reveals Contraceptive-Induced Alteration of Cervicovaginal Gene Expression in a Randomized Trial

Front Reprod Health. 2022 Mar 3:4:781687. doi: 10.3389/frph.2022.781687. eCollection 2022.

Authors

Christina Balle¹, Prachi M Gupta², Gregory K Tharp², Sydney A Nelson², Iyaloo N Konstantinus^{1

3}, Katie Lennard⁴, Shameem Z Jaumdally¹, Anna-Ursula Happel¹, Shaun L Barnabas^{1

5

6}, Katherine Gill⁵, Linda-Gail Bekker⁵, Jo-Ann S Passmore^{1

7}, Heather B Jaspan^{1

8

9}, Steven E Bosinger^{2

10

11}

Affiliations

¹ Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
² Yerkes Genomics Core Laboratory, Yerkes National Primate Research Center, Atlanta, GA, United States.
³ Namibia Institute of Pathology, Windhoek, Namibia.
⁴ Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
⁵ Desmond Tutu Health Centre, University of Cape Town, Cape Town, South Africa.
⁶ Family Clinical Research Center, Stellenbosch University, Tygerberg, South Africa.
⁷ National Health Laboratory Service, Cape Town, South Africa.
⁸ Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States.
⁹ Department of Pediatrics and Global Health, University of Washington, Seattle, WA, United States.
¹⁰ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, United States.
¹¹ Emory Vaccine Center, Emory University, Atlanta, GA, United States.

Abstract

Hormonal contraceptives (HCs) are vital in managing the reproductive health of women. However, HC usage has been linked to perturbations in cervicovaginal immunity and increased risk of sexually transmitted infections. Here, we evaluated the impact of three HCs on the cervicovaginal environment using high-throughput transcriptomics. From 2015 to 2017, 130 adolescent females aged 15-19 years were enrolled into a substudy of UChoose, a single-site, open-label randomized, crossover trial (NCT02404038) and randomized to injectable norethisterone-enanthate (Net-En), combined oral contraceptives (COC), or etonorgesterol/ethinyl-estradiol-combined contraceptive vaginal ring (CCVR). Cervicovaginal samples were collected after 16 weeks of randomized HC use and analyzed by RNA-Seq, 16S rRNA gene sequencing, and Luminex analysis. Participants in the CCVR arm had a significant elevation of transcriptional networks driven by IL-6, IL-1, and NFKB, and lower expression of genes supporting epithelial barrier integrity. An integrated multivariate analysis demonstrated that networks of microbial dysbiosis and inflammation best discriminated the CCVR arm from the other contraceptive groups, while genes involved in epithelial cell differentiation were predictive of the Net-En and COC arms. Collectively, these data from a randomized trial represent the most comprehensive "omics" analyses of the cervicovaginal response to HCs and provide important mechanistic guidelines for the provision of HCs in sub-Saharan Africa.

Keywords: HIV; South Africa; adolescents; cervicovaginal environment; hormonal contraception; randomized trial; systems biology.

Grants and funding

T32 GM008169/GM/NIGMS NIH HHS/United States