The cervical microbiome mediates hormonal increases in HIV1 susceptibility

宫颈微生物组介导 HIV1 易感性荷尔蒙增加

• 批准号: 8317886
• 负责人: Daniel N Frank
• 金额: $ 7.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317886
• 关键词: Age; Antigens; Bacteria; Bacterial Genes; Bacterial Genome; Blood; CD4 Positive T Lymphocytes; CXCR4 gene; Cells; Cervical; Cervix Uteri; Chemokine (C-C Motif) Receptor 5; Communities; DNA Sequence; Epithelium; Estrogens; Exhibits; Female; Fluorescent in Situ Hybridization; Gene Expression; Gene Expression Profile; Genes; Genital system; HIV-1; HLA-DR Antigens; Heterosexuals; Homeostasis; Hormonal; Human; Immune; Infection; Irrigation; Link; Measures; Mediating; Menopause; Messenger RNA; Metagenomics; Methods; Microbe; Microbial Biofilms; Microscopy; Modification; Mucous Membrane; Mucous body substance; Observational Study; Phylogenetic Analysis; Population; Postmenopause; Predisposition; Premenopause; Prevalence; Receptor Signaling; Research Personnel; Risk; Role; Sampling; Sequence Analysis; Signal Pathway; Signal Transduction; Specimen; T-Lymphocyte; Taxon; Testing; Tissues; Toll-like receptors; Transcript; Woman; antimicrobial; chemokine; chemokine receptor; density; gamma-Chemokines; immune function; microbial; microbial community; microbiome; microorganism antigen; novel; rRNA Genes; reproductive; transmission process

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.

描述（由申请人提供）：绝经期和宫颈阴道 (CV) 微生物群落失衡均与 HIV-1 感染风险增加相关。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)（一种 HIV-1 辅助受体）的 CD4+ T 淋巴细胞丰度升高。由于绝经后出现的低雌激素与 CV 微生物群的明显变化有关，因此我们的主要目标是确定共生的 CV 微生物群落是否介导绝经期与女性生殖道中 CCR5+CD4+ T 细胞数量增加之间的关联。我们假设，更年期依赖性的先天粘膜免疫功能抑制改变了宫颈阴道粘膜所暴露的微生物和微生物产物的类型和数量。由此产生的新型微生物抗原负担的增加进一步推测会损害宫颈免疫稳态，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CV灌洗和宫颈组织标本的高通量宏基因组分析进行测试，以实现以下具体目标： 目标 1. 确定宫颈阴道微生物群组成的改变是否与 CD4+ T 淋巴细胞水平升高相关表达趋化因子辅助受体（例如 CCR5、CXCR4）或激活标记物（例如 HLA-DR、CD38）。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. 通过比较绝经前和绝经后女性，确定宫颈粘膜上皮和常驻微生物群的基因表达模式是否存在差异。 公共卫生相关性：更年期和通常栖息在女性生殖道的细菌群落失衡都与 HIV-1 感染风险增加相关。最近的研究表明，绝经后妇女的免疫细胞（某些 T 淋巴细胞）丰度升高，易受 HIV-1 感染；然而，为什么会发生这种情况尚不清楚。我们假设宫颈阴道细菌的这些变化增加了宫颈中这些 HIV-1 易感 T 淋巴细胞的数量，从而增加了 HIV-1 向女性异性传播的风险。通过对明确人群的观察研究，我们将使用高通量DNA测序方法和先进的显微镜来检验这一假设，以全面确定更年期是否导致：1）不同种类的细菌栖息在女性生殖道中； 2）不同细菌基因的表达；和/或3)宫颈基因表达的改变。