The Vaginal Microbiome: Disease, Genetics and the Environment

描述：阴道是一个与环境相互作用的界面，因此被保护性上皮表面覆盖。该表面继而被细菌和其他微生物定殖，其通过多种机制用于进一步保护宿主免受病原体的入侵。正常阴道微生物区系的改变，特别是与细菌性阴道病相关的微生物区系的改变，被认为是导致妊娠中期自发性流产和自发性早产的风险的原因。此外，阴道微生物组的改变可能会增加某些病原体传播的可能性，包括人类免疫缺陷病毒1型（HIV-1）。宿主条件存在生理变化（例如，绝经和怀孕），其作为“正常”植物群变化的潜在选择性条件开始被研究，其对疾病易感性和传播的影响仍有待更明确地阐明。慢性异常生理状态的影响（例如，糖尿病）对正常阴道植物群的影响还没有很好的描述或研究。最后，一个几乎未被探索的领域是在正常和生理改变的情况下，遗传对建立和维持“正常”阴道植物群的贡献，包括种族/民族。拟议的研究将解决我们知识的差距，并阐明阴道微生物组如何导致不同人群中的不良产科结局和性传播疾病。该项目的目标是回答以下问题：具体目标1。宿主的基因是否有助于阴道微生物组的组成？我们假设，一个女人的遗传组成显着影响某些寄生虫，寄生虫和病原微生物的能力，殖民和/或感染生殖道。该目标分为2个子目标，其中第一个子目标将比较和量化大西洋中部双胞胎登记处（MATR）中单卵（MZ）和双卵（DZ）双胞胎阴道中的微生物种群。第二个子目标将利用从DZ和MZ双胞胎收集的样本解决阴道，口腔和胃肠道微生物组之间是否存在关系的问题。具体目标2。阴道微生物组的哪些变化与宿主的常见生理扰动或非感染性病理状态相关？我们假设，“改变”的生理（怀孕，绝经）和病理（慢性疾病，子宫切除术）条件，或环境“暴露”（外源性激素，抗生素，慢性免疫抑制剂，吸烟，冲洗）可以并经常可以预见地改变阴道微环境。这些改变反过来又会导致阴道内微生物种群的改变。微生物种群的变化可能对受影响个体的自发和未来健康产生积极或更可能消极的影响。我们将描述这些“改变的”生理和病理条件的影响，以及环境暴露对阴道微生物组组成的影响，并测试它们导致阴道微生物组可预测变化的假设。将评价微生物组的分子分析与基于Amsel标准和Nugent评分的实验室结果之间的关系。具体目标3。阴道微生物组的哪些变化与相关传染病和病症相关？我们将测试传染病可预测地改变阴道微生物组的假设，并且这些变化对疾病过程产生影响。我们还将检验阴道微生物组对某些相关传染病的易感性有影响的假设。在此特定目标中进行的研究将为生理，病理，环境和种族/种族因素及其相互作用的影响建模提供平台，以确定阴道微生物组。除了提供关键的描述性数据外，这将是一个产生假设的具体目标。我们将分析以下人群的阴道微生物组：正常育龄妇女;具有常见病理状况的同龄妇女（例如，阴道病、阴道炎、病毒感染、细菌性STD）;三种不同种族/人种的女性：欧洲高加索人、非洲裔美国人和墨西哥西班牙裔。我们将使用高通量“nextgen”测序技术的组合来解决这些问题，包括罗氏454 FLX和目前安装在VCU核酸研究设施中的升级的Illumina基因组分析仪II仪器。

DESCRIPTION: The vagina is an interactive interface with the environment, and as such is covered by a protective epithelial surface. This surface, in turn, is colonized by bacteria and other microorganisms which, through a variety of mechanisms serve to further protect the host from invasion by pathogens. Alterations in the normal vaginal microflora, particularly those associated with bacterial vaginosis, are thought to contribute to risk of spontaneous pregnancy loss in the second trimester and spontaneous preterm birth. Additionally, alterations in the vaginal microbiome may increase the likelihood of transmission of certain agents including human immunodeficiency virus type 1 (HIV-1). There are physiologic alterations in host condition (e.g., menopause and pregnancy), which are beginning to be investigated as potential selective conditions for change in the "normal" flora, and their impact on disease susceptibility and transmission remains to be more definitively elucidated. The effects of chronically abnormal physiologic states (e.g., diabetes mellitus) on normal vaginal flora have not been well described or studied. Finally, an almost unexplored area of inquiry is the genetic contribution, including race/ethnicity, to the establishment and maintenance of a "normal" vaginal flora, under normal and physiologically altered circumstances. The proposed research will address gaps in our knowledge and shed light on how the vaginal microbiome contributes to adverse obstetrical outcomes and sexually transmitted disease in diverse populations. The aims of the project are intended to answer the following questions: Specific Aim 1. Do the genes of the host contribute to the composition of the vaginal microbiome? We hypothesize that a woman's genetic composition significantly affects the ability of certain commensal, parasitic and pathogenic microbes to colonize and/or infect the genital tract. This aim is divided into 2 subaims, the first of which will compare and quantify the microbial populations inhabiting the vaginas of monozygotic (MZ) and dizygotic (DZ) twins in the Mid Atlantic Twin Registry (MATR). The second subaim will address the question of whether there is a relationship between the microbiomes of the vagina, mouth and GI tract utilizing samples collected from the DZ and MZ twins. Specific Aim 2. What changes in the vaginal microbiome are associated with common physiological perturbations or non-infectious pathological states of the host? We hypothesize that "altered" physiologic (pregnancy, menopause) and pathologic (chronic disease, hysterectomy) conditions, or environmental "exposures" (exogenous hormones, antibiotics, chronic immunosuppressant, smoking; douching) can and often do predictably alter the vaginal microenvironment. These alterations in turn will lead to alterations in microbial populations within the vagina. Changes in the microbial populations may have impacts, positive or more likely negative, on the spontaneous and future well-being of the affected individual. We will characterize the effects of these "altered" physiologic and pathologic conditions, and environmental exposures exert on the composition of the vaginal microbiome, and test the hypothesis that they lead to predictable changes in the vaginal microbiome. The relationship between the molecular analysis of the microbiome and laboratory findings based on Amsel's criteria and the Nugent Score will be evaluated. Specific Aim 3. What changes in the vaginal microbiome are associated with relevant infectious diseases and conditions? We will test the hypothesis that infectious diseases predictably alter the vaginal microbiome, and that these changes have an impact on the disease process. We will also test the hypothesis that the vaginal microbiome has an impact on susceptibility to some relevant infectious diseases. The research to be conducted in this Specific Aim will provide a platform for modeling the impact of physiological, pathological, environmental and ethnic/racial factors, and their interactions, in determining the vaginal microbiome. In addition to providing critical descriptive data, this will be a hypothesis-generating Specific Aim. We will analyze the vaginal microbiomes of: normal women of reproductive age; women in the same age range with common pathological conditions (e.g., vaginosis, vaginitis, viral infections, bacterial STDs); women of three different ethnic/racial groups: European Caucasian, African-American, and Mexican Hispanic. We will address these questions using a combination of high throughput 'nextgen' sequencing technologies, including the Roche 454 FLX and the upgraded Illumina Genome Analyzer II instruments currently installed in the Nucleic Acids Research Facilities at VCU.