How sex, host microenvironment, and immune responses shape acquisition of genital bacteria that increase HIV risk

项目摘要 最近，几种与性传播无关的生殖器厌氧菌 感染（非性传播感染）与艾滋病毒的异性传播增加有关，可能是通过诱导免疫 增强HIV靶细胞活化和向生殖器粘膜募集的反应。项目的目标是 消除关于获得和持续携带这一新的艾滋病毒风险因素的关键知识差距。我们 长期目标是阐明生殖器微生物组组成的决定因素和生殖器微生物组的生物学特性。 将生殖器细菌与宿主对HIV的易感性联系起来的机制，并利用这些知识来开发 创新的方法来预防艾滋病。目的是了解异性传播的动态 生殖器细菌与艾滋病毒的风险，并确定非生物和生物因素的影响， 这些生殖器细菌在男性中的获得和持久性。我们的中心假设是 影响阴茎微生物组组成-包括生殖器细菌的获得，损失或持续存在 与艾滋病毒风险相关的可预测的基于一系列非生物和生物因素。该项目的基本原理是 通过了解决定特定物种的获得、丧失或持久性的非生物和生物因素， 通过对生殖器细菌的研究，我们将能够确定和制定新的战略，以防止或减少定植。 目标1。阐明生殖器细菌的性传播和阴茎的决定因素 性生活后的微生物我们将通过以下方式进行测试：（i）描述青少年中存在的生殖器细菌菌株 男孩在初次性行为之前和之后（n = 200）和（ii）确定性交前宿主（阴茎）的影响， 伴侣（阴道）生殖器pH值、氧合、水分、代谢物、抗菌伊加和微生物组 获得或持久性（1，8，和72小时后性）的生殖器细菌在主机（n = 106对夫妇）。 目标2.阐明抗菌治疗后阴茎微生物组的决定因素。我们将测试 这是通过比较治疗前和治疗后（第3、8和28天）1个对照组和4个对照组的阴茎微生物组来实现的。 治疗组，包括3种局部治疗：（i）2%克林霉素，（ii）1%H2O2，（iii）0.75%甲硝唑， 和（iv）口服替硝唑。 目标3：研究非生物和生物因素对阴茎微生物组对 使用体外模型的扰动。我们将通过增加以下内容来实现这一目标：（i）供体阴道微生物组， (ii)局部抗菌剂对器官型包皮模型中阴茎微生物组的影响，以评估非生物性 因素和细菌菌株对微生物组结果的影响。 我们认为，拟议的研究是创新的，因为它代表了对现状的背离。 通过阐明可传播的生态失调，并使用绝对丰度指标， 研究设计和一种新的共培养模型。这项拟议的研究意义重大，因为它是 预计将揭示性和抗菌剂如何影响阴茎微生物组以及是什么驱动结果。

PROJECT SUMMARY Recently, several genital anaerobic bacteria that are not classically associated with sexually transmitted infections (non-STI) were linked to increased heterosexual transmission of HIV, likely by inducing immune responses that enhances HIV target cell activation and recruitment to the genital mucosa. This project seeks to close critical knowledge gaps regarding acquisition and persistent carriage of this new HIV risk factor. Our long-term goals are to elucidate the determinants of genital microbiome composition and the biological mechanisms that link genital bacteria to host susceptibility to HIV, and to leverage this knowledge to develop innovative solutions to prevent HIV. The objective is to understand the heterosexual transmission dynamics of genital bacteria associated with HIV risk and to determine the abiotic and biotic factors that impact acquisition and persistence of these genital bacteria in men. Our central hypothesis is that perturbations affect penile microbiome composition—including acquisition, loss, or persistence of genital bacteria associated with HIV risk—predictably based a set of abiotic and biotic factors. The rationale for this project is that, by understanding the abiotic and biotic factors that determine acquisition, loss, or persistence of specific genital bacteria, we will be able to identify and develop new strategies to prevent or reduce colonization. Aim 1. Elucidate the sexual transmission of genital bacteria and the determinants of the penile microbiome after sex. We will test this by: (i) Characterize the genital bacteria strains present in adolescent boys before and after sexual debut (n = 200) and (ii) Determine the effect of pre-coital host (penile) and partner (vaginal) genital pH, oxygenation, moisture, metabolites, anti-bacteria IgA, and microbiome on the acquisition or persistence (1, 8, and 72 hour post-sex) of genital bacteria in the host (n = 106 couples). Aim 2. Elucidate the determinants of the penile microbiome after antimicrobial treatment. We will test this by comparing pre- and post- treatment (Day 3, 8, and 28) penile microbiomes in 1 control arm and 4 treatment arms, including 3 topical treatments: (i) 2% clindamycin, (ii) 1% H2O2, (iii) 0.75% metronidazole, and (iv) oral tinidazole. Aim 3. Validate the impact of abiotic and biotic factors on the penile microbiome response to perturbation using an in vitro model. We will achieve this aim by adding: (i) donor vaginal microbiome and (ii) topical antimicrobials to penile microbiome in organotypic foreskin model to assess the effect of abiotic factors and bacterial strains on microbiome outcome. The proposed research is innovative, in our opinion, because it represents a departure from the status quo by elucidating transmissible dysbiosis, and doing so with absolute abundance metrics, innovative study designs, and a novel co-culture model. The proposed research is significant because it is expected to reveal how sex and antimicrobials impact penile microbiome and what drives outcome.