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（由适用提供）：每年在美国有大约2000万个新的性传播感染（STI），这些感染（STI）为医疗保健系统增加160亿美元的医疗费用。尚未充分探索的女性预防性传播感染的一种方法是利用阴道微生物组的受保护特征。阴道菌群在防止病原生物定植中起着重要作用。阴道乳酸杆菌属。通过产生乳酸，一定程度地提供广谱抗菌活性， 它为病原体创造了酸性和敌对的环境。迄今为止，只有基于细菌种植技术或微观评估的研究可以描述阴道细菌与STI风险之间的临时关联。但是，大多数微生物物种（> 90％）抗培养和显微镜仅提供形态学信息。正如我们所提出的那样，阴道菌群的完全表征需要分子方法。我们已经使用元基因组分析表明乳酸杆菌的特定基因型。与衣原体感染和阴道微生物群的不稳定性有关。我们提出了一个新的假设，即除了低乳杆菌状态外，特定的乳酸基因型基因型与Stis的风险增加有关，并且由乳杆菌SPP产生的D和L型异构体的混合物。差异影响性传播感染风险。炎症可能会导致阴道上皮的破坏，从而使病原体进入更深的组织，因此，我们还假设与特定阴道菌群相关的局部免疫反应可能促进性传播感染。我们寻求利用1999年NIH的阴道菌群纵向研究收集的存档宫颈阴道灌洗（CVL）样品，其中3,620名女性接受了一年的季度评估。总共观察到681名妇女获得了一名事件沙眼衣原体（CT），淋病奈瑟氏菌（GC）或阴道（TV）生殖器感染。存储库样品为在一项供电的研究中获取性传播感染之前提供了一个独特的机会来表征阴道微生物组。我们将通过入射密度采样进行嵌套的病例对照研究。案件将被定义为发生事件性传播疾病的妇女，我们将在第一次STI检测前分析访问时的样本。控制措施将与年龄，种族和访问人数相匹配，并将是案件访问时没有发展性传播感染的女性。具体目的是（1）使用16S RRNA基因分析评估阴道微生物群和CT，GC和TV生殖器感染的发生率之间的关联； （2）比较病例和对照中的D-和L-乳酸异构体的水平； （3）研究乳杆菌（或其他细菌）的特定菌株是否使用元基因组分析与STI风险有关； （4）确定子宫颈免疫是否独立预测入射性传播感染。所有四个目标都将在综合行为数据的背景下进行建模。这项研究将对阴道微生物组在STI保护中的作用提供功能理解，并可能揭示防止性传播感染和改善妇女健康的新目标。