The cervical microbiome mediates hormonal increases in HIV1 susceptibility

描述（由申请人提供）：更年期和宫颈阴道（CV）微生物群落失衡与HIV-1感染风险增加有关。最近的研究表明，绝经后妇女表现出表达C-C趋化因子受体5型（CCR5）的CD4+ t淋巴细胞丰度升高，CCR5是一种HIV-1辅助受体。由于绝经后发生的低雌激素与CV微生物群的明显改变有关，我们的主要目的是确定共生CV微生物群落是否介导绝经与女性生殖道CCR5+CD4+ t细胞群升高之间的关联。我们假设，先天黏膜免疫功能的绝经依赖性抑制改变了暴露于宫颈阴道粘膜的微生物和微生物产物的类型和数量。由此导致的新型微生物抗原负担的增加进一步被假设为破坏宫颈免疫稳态，从而增加HIV-1靶细胞向宫颈粘膜下层的募集。这些假设将通过对宫颈灌洗和宫颈组织标本进行高通量宏基因组分析来验证，以实现以下具体目标：确定宫颈阴道微生物群组成的改变是否与表达趋化因子辅助受体（如CCR5、CXCR4）或激活标志物（如HLA-DR、CD38）的CD4+ t淋巴细胞水平升高有关。目标2。确定更年期是否与宫颈上皮附近细菌密度的改变有关。目标3。确定绝经前和绝经后妇女宫颈粘膜上皮和常驻微生物群的基因表达模式是否不同。

DESCRIPTION (provided by applicant): Both menopause and imbalances in cervicovaginal (CV) microbial communities are associated with increased risk of HIV-1 acquisition. Recent studies indicate that postmenopausal women exhibit elevated abundances of CD4+ T-lymphocytes expressing C-C chemokine receptor type 5 (CCR5), a HIV-1 coreceptor. Because low estrogen, as occurs following menopause, is linked to distinct alterations in the CV microbiota, our primary objective is to determine whether commensal CV microbial communities mediate the association between menopause and elevated populations of CCR5+CD4+ T-cells in the female reproductive tract. We hypothesize that menopause-dependent suppression of innate mucosal immune function alters the types and quantities of microbes and microbial products to which the cervicovaginal mucosa is exposed. The resulting increased burden of novel microbial antigens is further hypothesized to compromise cervical immune homeostasis, thereby increasing recruitment of HIV-1 target cells to the cervical sub-mucosa. These hypotheses will be tested using high-throughput, metagenomic analysis of CV lavage and cervical tissue specimens in order to accomplish the following specific aims: Aim 1. Determine whether an altered composition of the cervicovaginal microbiota is associated with elevated levels of CD4+ T-lymphocytes expressing chemokine coreceptors (e.g., CCR5, CXCR4) or activation markers (e.g., HLA-DR, CD38). Aim 2. Determine whether menopause is associated with altered densities of bacteria in proximity to the cervical epithelium. Aim 3. Determine whether gene expression patterns of cervical mucosal epithelia and resident microbiota differ in a comparison of premenopausal and postmenopausal women. PUBLIC HEALTH RELEVANCE: Both menopause and imbalances in the bacterial communities normally inhabiting the female reproductive tract are associated with increased risk of HIV-1 acquisition. Recent studies indicate that postmenopausal women exhibit elevated abundances of immune cells (certain T-lymphocytes) that are susceptible to HIV-1 infection; however, why this occurs is not known. We hypothesize those changes in cervicovaginal bacteria increase the quantities of these HIV-1 susceptible T-lymphocytes in the cervix, and thereby increase the risk of heterosexual transmission of HIV-1 to females. Through observational studies of well-defined human populations, we will test this hypothesis by using high-throughput DNA sequencing methods, along with advanced microscopy, to comprehensively determine whether menopause results in 1) different kinds of bacteria inhabiting the female reproductive tract; 2) expression of different bacterial genes; and/or 3) modification of cervical gene expression.