Pathogenesis of Bacterial Vaginosis in Women Who Have Sex with Women

描述（由申请人提供）：细菌性阴道病（BV）是美国最常见的阴道感染，估计患病率为30%。它与不良后果相关，包括早产、盆腔炎和性传播感染（STIs）（包括艾滋病毒）的风险增加。BV代表了阴道微生物群从以乳酸杆菌为主的物种向兼性（阴道加德纳菌；GV）和严格的厌氧细菌的转变。细菌性阴道炎在与女性发生性行为的女性中非常常见，它被认为是一种性传播感染。然而，细菌性阴道炎的发病机制尚不清楚。至于细菌性阴道炎是否作为“创始者”生物体获得阴道阴道病毒，从而导致与细菌性阴道炎相关的阴道微生物群发生复杂变化，细菌性阴道炎是否作为多微生物联合体传播，[或者细菌性阴道炎是否由影响阴道微生物群的行为因素引起]，这些问题仍然存在争议。GV作为兼性厌氧菌，可能能够耐受健康阴道微生物群的高氧化还原（氧化还原）潜力，而不像严格的厌氧菌（即其他bv相关细菌：BVAB）。与参与口腔疾病起始的兼性厌氧菌类似，GV可能在阴道微生物群中产生较低的氧化还原电位，从而导致乳酸菌显著减少和其他BVAB（通常可能以极低浓度存在）增加，从而导致BV综合征。WSW，特别是非裔美国WSW (AAWSW)，是研究细菌性阴道炎发病机制的一个独特人群，因为没有男性感染者，而非裔美国人种族是细菌性阴道炎的一个危险因素。我假设在AAWSW中性暴露于GV是导致与BV相关的复杂阴道菌群的煽动事件。为了验证这一假设，我提出了以下独立但相互关联的目标。[目的]利用培养不依赖的分子方法确定性活跃的AAWSW中最终导致BV的微生物事件序列。我推测，在发生BV的女性中，GV的出现及其相对丰度会在其他BVAB丰度增加之前增加。[目的2：确定特定GV寡型是否与性活跃的AAWSW中BV的发展相关。]鉴于GV可以在“正常”女性和BV女性中出现的相互矛盾的观察结果，我假设GV寡型在BV发展方面的致病潜力不同。这个由导师指导的、以患者为导向的研究职业发展奖项和研究目标旨在为我提供与培养无关的分子诊断学、生物信息学技术、临床微生物学和临床研究基础方面的高级培训。这个奖项所创造的机会将使我成为一名独立的转化研究研究者，具备必要的技能，能够道德地、准确地回答与细菌性脑膜炎发病机制相关的重要科学问题。确定细菌性阴道炎的确切致病因子对于适当治疗和预防不良后果至关重要。

DESCRIPTION (provided by applicant): Bacterial vaginosis (BV) is the most common vaginal infection in the United States, with an estimated prevalence of 30%. It is associated with adverse outcomes including preterm birth, pelvic inflammatory disease, and increased risk for sexually transmitted infections (STIs), including HIV. BV represents a shift in the vaginal microbiota from Lactobacillus-predominate species to facultative (Gardnerella vaginalis; GV) and strict anaerobic bacteria. BV is very common among women who have sex with women (WSW) and it is hypothesized to be an STI. However, the pathogenesis of BV remains unclear. It remains controversial as to whether BV results from acquisition of GV as the "founder" organism which subsequently leads to the complex changes in the vaginal microbiota associated with BV, whether BV is transmitted as a polymicrobial consortium, [or whether BV is caused by behavior factors influencing the vaginal microbiota]. GV, as a facultative anaerobe, may be able to tolerate the high oxidation-reduction (redox) potential of a healthy vaginal microbiome, unlike strict anaerobes (i.e. other BV-associated bacteria: BVAB). Similar to facultative anaerobes involved in the initiation of oral disease, it is possible that GV creates a lower redox potential in the vaginal microbiome which causes a marked decrease in lactobacilli and an increase in other BVAB (which may normally be present in very low concentrations), leading to the BV syndrome. WSW, [particularly African American WSW (AAWSW), are a unique population in which to study BV pathogenesis as there is no male equivalent to this infection and African American race is a risk factor for BV]. I hypothesize that sexual exposure to GV among AAWSW is the inciting event leading to the complex vaginal flora associated with BV. To test this hypothesis, I propose the following independent but inter-related aims. [Aim1: Use cultivation-independent molecular methods to determine the sequence of microbiological events culminating in BV among sexually active AAWSW. I hypothesize that the appearance of GV and its relative abundance will increase in women with incident BV prior to increases in the abundance of other BVAB.] [Aim 2: Determine if specific GV oligotypes are associated with the development of BV among sexually active AAWSW. I hypothesize that GV oligotypes differ in their pathogenic potential with regards to the development of BV given the conflicting observation that GV can be present in both "normal" women and women with BV.] This mentored, patient oriented research career development award and research aims are designed to provide me with advanced training in cultivation-independent molecular diagnostics, bioinformatics techniques, clinical microbiology, and the fundamentals of clinical research. The opportunities created by this award will allow me to become an independent translational research investigator with the skills necessary to ethically and accurately answer important scientific questions related to BV pathogenesis. Determining the exact causative agent(s) of BV is vital for the appropriate treatment and prevention of adverse outcomes.