Longitudinal Study of the Vaginal Microbiome Prior To Incident STI

性传播感染发生前阴道微生物组的纵向研究

• 批准号: 8963646
• 负责人: REBECCA M. BROTMAN
• 金额: $ 74.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963646
• 关键词: Affect; Age; Archives; Bacteria; Behavioral; Biological; Chlamydia Infections; Chlamydia trachomatis; Communities; Comparative Genomic Analysis; Data; Detection; Environment; Epithelium; Ethnic Origin; Evaluation; Female; Future; Genomics; Genotype; Gram' s stain; Healthcare Systems; High-Throughput Nucleotide Sequencing; Human; Immune response; Immunologic Markers; Immunologics; Incidence; Infection; Infection prevention; Infectious Agent; Inflammation; Inflammatory; Influentials; Irrigation; Isomerism; Lactic acid; Lactobacillus; Lead; Longitudinal Studies; Medical; Metagenomics; Microscopic; Microscopy; Modeling; Molecular; Mucous body substance; Neisseria gonorrhoeae; Nested Case-Control Study; Organism; Pathway interactions; Play; Predisposition; Prevention approach; Prevention trial; Production; Prospective Studies; Research; Risk; Role; Sampling; Sexually Transmitted Diseases; Techniques; Time; Tissues; Trichomonas vaginalis; United States National Institutes of Health; Urinary tract; Vagina; Visit; Woman; Women' s Health; antimicrobial; bactericide; bacteriocin; base; case control; cervicovaginal; cost; data modeling; density; genital infection; improved; metagenome; microbial; microbiome; novel; pathogen; pathogen exposure; prevent; public health relevance; rRNA Genes; repository; reproductive; routine Bacterial stain; therapy development; vaginal lactobacilli

 DESCRIPTION (provided by applicant): There are approximately 20 million new sexually transmitted infections (STIs) in the U.S. each year that add $16 billion in medical costs to the healthcare system. One approach to prevention of STIs in women that has not been fully explored is harnessing the protective features of the vaginal microbiome. The vaginal microbiota play an important role in preventing colonization by pathogenic organisms. Vaginal Lactobacillus spp. provide broad-spectrum antimicrobial activity in part through their production of lactic acid, which creates an acidic and hostile environment to pathogens. To date, only studies based on bacterial cultivation techniques or microscopic evaluation are available to describe the temporal association between the vaginal bacteria and risk of STI. However, a majority of microbial species (>90%) resist cultivation and microscopy only provides morphological information. Complete characterization of the vaginal microbiota requires molecular approaches as we propose. We have shown using metagenomic analysis that specific genotypes of Lactobacillus spp. are associated with both chlamydial infection and vaginal microbiota instability. We are putting forth a novel hypothesis that, in addition to a low-Lactobacillus state, specific Lactobacillus genotypes are associated with increased risk for STIs, and that the mixture of D- and L- lactate isomers produced by Lactobacillus spp. differentially affects STI risk. Inflammation may cause destruction of the vaginal epithelium, allowing pathogens to access deeper tissues, and therefore, we also hypothesize that local immune responses associated with specific vaginal microbiota may facilitate STIs. We seek to utilize archived cervicovaginal lavage (CVL) samples collected from the 1999 NIH Longitudinal Study of Vaginal Flora in which 3,620 women were followed for one year with quarterly assessments. A total of 681 women were observed to acquire an incident Chlamydia trachomatis (CT), Neisseria gonorrhea (GC), or Trichomonas vaginalis (TV) genital infection. The repository samples provide a unique opportunity to characterize the vaginal microbiome prior to acquisition of STIs in a well-powered study. We will conduct a nested case-control study with incidence density sampling. Cases will be defined as women who had an incident STI and we will analyze the sample at the visit prior to the first STI detection. Controls will be matched on age, ethnicity and visit number to cases and will be women who did not develop a STI by the time of the case visit. Specific aims are to (1) Evaluate the association between vaginal microbiota and incidence of CT, GC, and TV genital infection using 16S rRNA gene analysis; (2) Compare levels of D- and L-lactic acid isomers in cases and controls; (3) Investigate if specific strains of Lactobacillus (or other bacterium) are associated with STI risk using metagenomic analysis; (4) Determine if cervicovaginal immune responses independently predict incident STIs. All four aims will be modeled in the context of comprehensive behavioral data. This study will provide a functional understanding of the vaginal microbiome's role in STI protection and may reveal novel targets to prevent STIs and improve women's health.

 描述(由申请人提供)：美国每年约有2000万新发性传播感染(STI)，这些疾病给医疗保健系统增加了160亿美元的医疗成本。预防女性性传播感染的一种方法尚未得到充分探索，那就是利用阴道微生物群的保护功能。阴道微生物区系在防止病原微生物定植方面起着重要作用。阴道乳杆菌属部分通过产生乳酸提供广谱抗菌活性， 这为病原体创造了一个酸性和敌意的环境。到目前为止，只有基于细菌培养技术或显微镜评估的研究才能描述阴道细菌与性传播感染风险之间的时间相关性。然而，大多数微生物种类(&gt；90%)抵抗培养，显微镜只提供形态信息。如我们所建议的那样，阴道微生物区系的完整特征需要分子方法。我们已经利用元基因组分析表明，乳杆菌属的特定基因类型。与衣原体感染和阴道微生物区系不稳定有关。我们提出了一个新的假设，即除了低乳酸菌状态外，特定的乳杆菌基因型会增加性传播感染的风险，而且乳杆菌产生的D-和L-乳酸异构体的混合物。不同程度地影响性传播感染风险。炎症可能导致阴道上皮的破坏，使病原体能够进入更深的组织，因此，我们还假设与特定的阴道微生物区系相关的局部免疫反应可能促进性传播感染。我们试图利用从1999年NIH阴道真菌纵向研究中收集的宫颈阴道灌洗液(CVL)存档样本，在该研究中，3,620名女性接受了为期一年的季度评估。共有681名妇女被观察到感染沙眼衣原体(CT)、奈瑟菌淋病(GC)或阴道毛滴虫(TV)生殖器感染。在一项强有力的研究中，在获得性传播感染之前，储存库样本提供了一个独特的机会来表征阴道微生物群。采用病例密度抽样法进行嵌套病例对照研究。病例将被定义为发生过性传播感染的妇女，我们将在第一次检测到性传播感染之前分析就诊时的样本。对照将在年龄、种族和就诊次数方面与病例相匹配，并将是在病例就诊时尚未发生性传播感染的妇女。具体目标是(1)使用16SRRNA基因分析来评估阴道微生物群与CT、GC和TV生殖器感染的发病率之间的关系；(2)比较病例和对照中D-乳酸和L-乳酸异构体的水平；(3)利用元基因组分析来调查特定的乳杆菌(或其他细菌)菌株是否与性传播感染的风险相关；(4)确定宫颈阴道免疫反应是否独立地预测STI的发生。所有四个目标都将在综合行为数据的背景下建模。这项研究将从功能上了解阴道微生物群在性传播感染保护中的作用，并可能揭示预防性传播感染和改善妇女健康的新靶点。