Project description:Time-course expression analysis profiling whole blood samples collected from healthy South African adolescents while monitoring their potential acquisition of a Mycobacterium tuberculosis infection.
Project description:Use of hormonal contraceptives (HC) could alter the bacterial community, immune response and epithelial barrier integrity of the female genital tract (FGT) mucosal environment, leading to increased susceptibility to sexually transmitted infections (STIs), including HIV. Here, we tested whether use of three types of HCs, injectable Net-En, combined oral contraceptives (COC) and NuvaRing, a combined contraceptive vaginal ring (CCVR), led to distinct patterns in FGT host transcriptomics transcriptome in South African adolescent females. In an intention-to-treat analysis, we observed few changes in endocervical gene expression in the Net-En and COC groups. Relative to the COC and Net-En arms, samples from the CCVR arm had 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 of the cervicovaginal microbiome, transcriptome and cytokines demonstrated that networks of microbial dysbiosis and inflammation accurately 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.
Project description:Systems analysis of the female genital tract reveals differential expression of inflammatory and epithelial barrier genes in South African adolescents randomized to injectable, oral or vaginal ring contraception
Project description:Progestin-based contraception may increase the risk of vaginal HIV acquisition to a level greater than the progesterone-rich luteal phase of the menstrual cycle, which has been demonstrated to have a significantly higher transmission rate compared to the follicular phase. We used pig-tailed macaque (Macaca nemestrina) model to evaluate the effects of administration of the oral the combined oral contraceptives (COCs) depot medroxyprogesterone acetate (DMPA) and levonorgestrel (LNG) on mucosal factors that influence HIV susceptibility. We compared the pH and vaginal epithelial thickness data from previous studies, and evaluated contraception-induced molecular changes in the vagina using transcriptional and cytokine profiling. The administration of DMPA caused a pronounced thinning of the vaginal epilthelium relative to measurements takein in the follicular or luteal phase. DMPA also induced a significant increase in vaginal IL10 expression. Lastly, using RNA-Seq analyses of vaginal biopsies, we noted that both DMPA- and LNG-based contraception induced a signature of gene expression similar to that of the luteal phase, only more exacerbated, and including widespread down-regulation of HIV-restriction genes. Use of progestin-based contraception might engender a milieu that poses an increased risk of HIV transmission than that of the luteal phase via vaginal thinning, induction of immunosuppressive cytokines, and widespread suppression of HIV restriction factors.