Mechanisms regulating episodic breaches of protective vaginal microbiome by BV

BV 调节保护性阴道微生物组偶发性破坏的机制

• 批准号: 8519050
• 负责人: Ying-Ying Wang
• 金额: $ 5.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-27 至 2014-04-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519050
• 关键词: Acidity; Address; Amines; Antibiotics; Antibodies; Bacteria; Bacterial Vaginosis; Cells; Characteristics; Communities; Complement; Culture Media; Development; Diffusion; Disease; Disease remission; Entire transverse folds of palate; Epidemiology; Epithelial; Event; Exposure to; Fluids and Secretions; Goals; Gonorrhea; Gram-Negative Bacteria; HIV; In Vitro; Incidence; Lactic acid; Lactobacillus; Liquid substance; Measures; Mediating; Menstruation; Methods; Microbe; Minority; Monitor; Mucous body substance; Participant; Play; Population; Predisposition; Relapse; Reporting; Reproductive Health; Research; Research Personnel; Resolution; Risk; Role; Sampling; Sexually Transmitted Diseases; Simplexvirus; Specificity; System; Testing; Time; Trichomonas; Vaccines; Vagina; Vaginal Douching; Woman; cervicovaginal; density; design; experience; in vivo; innovation; male; method development; microbial community; microbicide; microbiome; pathogen; prevent; restoration; transmission process; vaginal fluid; vaginal lactobacilli

DESCRIPTION (provided by applicant): In women with a healthy vaginal microbiome, lactobacillus communities acidify the vagina with lactic acid, a potent and broad-spectrum microbicide that reinforces the mucosal barrier to sexually transmitted infections (STIs). However, for at least one-third of women worldwide (and >50 percent of black women), protective lactobacilli are displaced by a dense mixture of Gram-variable and Gram-negative bacteria, often leading to a condition known as bacterial vaginosis (BV). BV markedly increases susceptibility to virtually all STIs, including HIV. Although BV can be treated with antibiotics, relapse occurs frequently, with ~2 BV episodes per month. How vaginal bacterial communities shift rapidly between protective lactobacilli and unprotective BV is not understood, and no method currently exists for preventing BV. This project seeks to identify factors that cause the rapid shifts between vaginal bacterial communities. The results may guide the development of much needed methods to prevent BV and thereby substantially reduce STI transmission rates. The overall hypothesis is that these shifts result from antagonistic actions between lactobacilli and BV-associated bacteria that are mediated by secreted inhibitory factors; preliminary evidence suggests lactic acid secreted by lactobacilli, and amines secreted by BV microbes, may be two such factors. To test this hypothesis, qPCR analysis will be used to quantify the specificity and potency of inhibitory factors present in ex vivo healthy, lactobacillus-dominated vaginal secretions against BV-associated bacteria, and conversely factors in ex vivo BV secretions that inhibit lactobacilli (Aim 1). In addition, the dynamics of BV onset (Aim 2) will be investigated by monitoring the depletion of lactobacilli, and the decrease in inhibition of BV-associated bacteria in vaginal secretions during menses or following vaginal douching (two events associated with BV onset). Similarly, BV remission (Aim 3) will be studied by monitoring antagonistic inhibitory factors in vaginal secretions as lactobacilli recover following a BV episode. The use of fresh, minimally-perturbed ex vivo vaginal secretions to investigate the actions of inhibitory factors represents a significant innovation; most prior research has been performed in vitro in growth media, which fails to capture the unique mixture of cells (including symbiotic microbial communities), inhibitory factors and mucus fluid present in vivo.

描述（由申请人提供）：在拥有健康阴道微生物组的女性中，乳酸菌群落会用乳酸酸化阴道，乳酸是一种强效广谱杀菌剂，可增强粘膜屏障，抵御性传播感染 (STI)。然而，对于全世界至少三分之一的女性（以及 > 50% 的黑人女性）来说，保护性乳酸杆菌被革兰氏变异菌和革兰氏阴性菌的密集混合物取代，通常会导致细菌性阴道病 (BV) 的病症。 BV 显着增加对几乎所有性传播感染（包括艾滋病毒）的易感性。尽管细菌性阴道炎可以用抗生素治疗，但复发频繁，每月约有 2 次细菌性阴道炎发作。阴道细菌群落如何在保护性乳酸杆菌和非保护性 BV 之间快速转变尚不清楚，目前也没有预防 BV 的方法。该项目旨在找出导致阴道细菌群落快速变化的因素。研究结果可能会指导开发急需的方法来预防 BV，从而大幅降低 STI 传播率。总体假设是，这些转变是由分泌的抑制因子介导的乳酸杆菌和 BV 相关细菌之间的拮抗作用引起的。初步证据表明，乳酸杆菌分泌的乳酸和细菌性阴道炎微生物分泌的胺可能是其中的两个因素。为了检验这一假设，将使用 qPCR 分析来量化离体健康、以乳酸杆菌为主的阴道分泌物中存在的针对 BV 相关细菌的抑制因子的特异性和效力，以及相反的离体 BV 分泌物中抑制乳酸杆菌的因子（目标 1）。此外，BV 发作的动态（目标 2）将是 通过监测月经期间或阴道冲洗后阴道分泌物中乳酸杆菌的消耗以及 BV 相关细菌抑制的减少（与 BV 发病相关的两个事件）进行研究。同样，BV 缓解（目标 3）将通过监测 BV 发作后乳酸杆菌恢复时阴道分泌物中的拮抗抑制因子来研究。使用新鲜的、干扰最小的离体阴道分泌物来研究抑制因子的作用是一项重大创新；大多数先前的研究都是在体外的生长培养基中进行的，无法捕获体内存在的细胞（包括共生微生物群落）、抑制因子和粘液的独特混合物。