The effect of the penile microbiome on BV, GUD, and genital epithelial trauma

描述（由申请人提供）：医学男性包皮环切术（MMC）将非洲男性异性恋感染艾滋病毒的风险降低了60%。在肯尼亚的MMC试验和乌干达的MMC试验中，包皮环切的男性阴茎厌氧菌的患病率和数量都较低，其中一些细菌与细菌性阴道病（BV）有关。这种益处转移到包皮环切术男性的女性性伴侣身上，她们感染细菌性阴道炎的风险降低了40-60%。MMC使生殖器溃疡病（GUD）降低37-52%，使包皮环切男性女性性伴侣的GUD降低32%。在我们在肯尼亚的试验中，与疱疹性GUD相比，Fusobacteria和Sneathia从非疱疹性GUD中恢复的几率要高6倍。这两种与细菌性阴道炎相关的厌氧菌在未割包皮的男性中更为常见，并导致口腔溃疡和牙周病。它们的减少可能解释了包皮环切术男性及其女性性伴侣中非疱疹性GUD的减少。在我们在肯尼亚的研究中，30-50%的男性和女性发生阴道或阴茎皮肤割伤、擦伤、划伤和出血，而在包皮环切手术的男性及其女性性伴侣中，这一比例减少了40-60%。阴茎厌氧细菌是MMC与BV和GUD减少之间的共同联系，也可以解释割礼男性及其性伴侣生殖器上皮损伤的减少。我们建议确定在什么条件下阴茎微生物组导致男性及其女性性伴侣的BV， GUD和生殖器上皮损伤。在204对异性恋夫妇的前瞻性队列中，我们将在一年内使用16S rRNA基因的高温标记测序四次测量阴茎和阴道微生物组。我们将（目标1）确定阴茎微生物组如何导致BV、GUD和生殖器上皮损伤，以及影响这些关联的因素。我们将（目标2）定义导致阴茎微生物组随时间和男性变化的因素。我们将（目标3）将特定的阴茎和阴道细菌映射到生殖器炎症细胞因子水平的增加，并阐明炎症细胞因子与生殖器上皮损伤之间的联系。我们需要确定MMC如何减少这些HIV感染的辅助因素，从而在未割包皮的男性中获得益处，并增强MMC的保护作用。改善阴茎微生物组健康的药理学干预可能包括全身或局部抗菌剂，或含有细胞因子调节剂的杀微生物剂。我们需要识别特定的细菌，以确定适当的抗菌剂类别，以及是否可以改变引起炎症的程度或类型。如果特定的行为——比如女性经期性行为或生殖器卫生——与有害阴茎细菌的种类或数量有关，那么行为干预将被测试。这项研究产生的干预措施的潜在好处是：(1)通过减少细菌性阴道炎、GUD和生殖器上皮损伤作为感染的辅助因素，减少HIV的获取和传播；(2)改善妊娠结局和泌尿生殖系统健康。

DESCRIPTION (provided by applicant): Medical male circumcision (MMC) reduces the risk of heterosexual HIV acquisition in African men by 60%. In both our MMC trial in Kenya and the Ugandan MMC trial, circumcised men had lower prevalence and amount of penile anaerobic bacteria, several species of which are associated with Bacterial vaginosis (BV). The benefit is transferred to female sex partners of circumcised men, who had a 40-60% reduced risk of BV. MMC reduced genital ulcer disease (GUD) by 37-52%, and reduced GUD in female sex partners of circumcised men by 32%. Among men in our trial in Kenya, Fusobacteria and Sneathia had 6-fold greater odds of recovery from non-herpetic GUD compared to herpetic GUD. These two BV-related anaerobes are more common among uncircumcised men, and cause oral ulcers and periodontal disease. Their reduction may explain the reduction in non-herpetic GUD in circumcised men and their female sex partners. Cuts, abrasions, scratches, and bleeding of the vaginal or penile skin occur in 30-50% of men and women in our studies in Kenya, and are reduced by 40-60% among circumcised men and their female sex partners. Penile anaerobic bacteria are a common link between MMC and reductions in BV and GUD, and may also explain the reduced genital epithelial trauma among circumcised men and their sex partners. We propose to identify under what conditions the penile microbiome leads to BV, GUD, and genital epithelial trauma in men and their female sex partners. Within a prospective cohort of 204 heterosexual couples, we will measure the penile and vaginal microbiome four times over a one year period using pyrotag sequencing of the 16S rRNA gene. We will (Aim 1) determine how the penile microbiome leads to BV, GUD, and genital epithelial trauma, and factors that influence these associations. We will (Aim 2) define factors causing variation in the penile microbiome over time and across men. We will (Aim 3) map specific penile and vaginal bacteria to increased genital inflammatory cytokine levels, and elucidate the link between inflammatory cytokines and genital epithelial trauma. We need to determine how MMC reduces these co-factors for HIV infection to achieve benefits among uncircumcised men and to augment the protective effect of MMC. Pharmacologic interventions to improve penile microbiome health may include systemic or topical antimicrobials, or microbicides incorporating cytokine modulators. We need to identify specific bacteria to determine appropriate classes of antimicrobials, and whether the extent or type of inflammation induced can be modified. If specific behaviors - such as sex during a woman's menstruation or genital hygiene - are associated with types or amounts of harmful penile bacteria, then behavioral interventions will be tested. The potential benefits of interventions stemming from this investigation are: (1) reduced HIV acquisition and transmission through reduction of BV, GUD, and genital epithelial trauma as co-factors for infection, and (2) improved pregnancy outcomes and genitourinary health.