Prospective Epidemiologic Study of Novel Etiologic Agents of Pelvic Inflammatory Disease

盆腔炎新病因的前瞻性流行病学研究

• 批准号: 10471222
• 负责人: DAVID Neal FREDRICKS
• 金额: $ 82.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471222
• 关键词: 16S ribosomal RNA sequencing; Abscess; Adnexal Mass; Affect; Anaerobic Bacteria; Archives; Atopobium vaginae; Bacteria; Bacterial Vaginosis; Behavioral; Biological Assay; Case Study; Cell Culture Techniques; Cervical; Characteristics; Chlamydia trachomatis; Clinical; Complement; Complication; Detection; Development; Diagnosis; Diagnostic; Direct Costs; Ectopic Pregnancy; Endometrial; Endometritis; Endometrium; Etiology; Facilities and Administrative Costs; Female; Fever; Future; Gene Expression; Genes; Gynecologic; High Risk Woman; High-Throughput Nucleotide Sequencing; Histologic; Human; Infection; Infertility; Inflammation; Inflammatory; Knowledge; Link; Literature; Mammalian Oviducts; Measures; Metagenomics; Methods; Microbe; Mobiluncus; Modeling; Molecular; Mycoplasma genitalium; Neisseria gonorrhoeae; Organism; Organoids; Patients; Pelvic Inflammatory Disease; Phase; Pilot Projects; Population; Population Attributable Risks; Postpartum Period; Prevention strategy; Preventive treatment; Prevotella; Primary Prevention; Prospective Studies; Prospective cohort study; Publishing; Recording of previous events; Recurrence; Reporting; Risk; Role; Salpingitis; Sampling; Secondary Prevention; Sexually Transmitted Diseases; Shotgun Sequencing; Specimen; Surveys; System; Technology; Testing; Time; Tissues; Translating; Trichomonas vaginalis; Vagina; Woman; aged; bacterial community; base; case control; chronic pelvic pain; clinical practice; cohort; design; disease diagnosis; disorder risk; endometrial organoid; epidemiology study; follow-up; genetic signature; high risk; microorganism; nano-string; next generation sequencing; novel; novel diagnostics; overexpression; pathogen; predictive modeling; prevent; prospective; rRNA Genes; reproductive; reproductive tract; response; routine screening; tubal infertility; vaginal microbiome; vaginal microbiota; young woman

Haggerty, Catherine L. Project Abstract Pelvic Inflammatory Disease (PID) is the frequent infection and inflammation of the upper genital tract among young women that often results in infertility, chronic pelvic pain, and recurrent PID. PID is a recognized complication of Chlamydia trachomatis and Neisseria gonorrhoeae infections, yet up to 70% of cases are idiopathic. An association between bacterial vaginosis (BV) and PID is recognized, however few studies have examined the specific vaginal bacteria most linked to PID, particularly focusing on vaginal bacteria that may resist lab cultivation. Cross-sectional evidence implicates Mycoplasma genitalium (MG) and the protozoan Trichomonas vaginalis (TV) as potential causes of PID, but prospective studies are lacking. We propose a prospective cohort study of 1,199 women considered at high risk for sexually transmitted infection who were actively followed three years for PID development. We will develop and apply to samples a panel of quantitative (qPCR) assays for suspect pathogens, including newly identified BV-associated bacteria, MG, and TV based on our pilot studies and broad-range 16S rRNA gene PCR with next generation sequencing and shotgun sequencing in the discovery phase. We will apply the NanoString nCounter inflammation panel to endometrial samples to determine whether particular inflammatory genes are overexpressed in samples from women with PID compared to women without PID in a bacterial species-specific fashion. We will complement our human studies with fallopian tube and endometrial organoid models, allowing us to directly assess how candidate pathogens interact with tissues of the female upper reproductive tract to induce inflammation. Our aims are to: 1) Develop a panel of candidate microbes for the prediction of PID using broad-range 16S rRNA gene PCR with high throughput sequencing (bacteria) and metagenomics shotgun sequencing (all microbes); 2) Determine whether the presence and quantity of vaginal pathogens in our candidate panel are associated with incident PID using sensitive qPCR, and whether the presence of these candidate pathogens in endometrial tissue is associated with an inflammatory gene signature in patients with PID; 3) Develop a model for the prediction of PID; 4) Determine the population attributable fraction (PAF) of PID due to each pathogen in our panel, CT, and NG; and 5) Determine the inflammatory potential of candidate PID pathogens in fallopian tube and endometrial organoid culture models where microbes are inoculated and inflammatory gene expression is assessed. This will be the first prospective study of PID to apply state-of-the-art qPCR assays and vaginal microbiome profiling, creating the potential for pathogen discovery and imparting a greater understanding of PID etiology. Further, we propose the first study to use fallopian tube organoids and NanoString technology to study PID. Testing for non-gonococcal, non-chlamydial pathogens is not routine, and knowledge gained from our study may identify novel diagnostic targets for PID with the potential to optimize future diagnostic, preventive, and treatment approaches.

作者：Catherine L. 项目摘要 盆腔炎是一种常见的上生殖道感染和炎症。 年轻女性往往会导致不孕、慢性盆腔疼痛和反复发作的盆腔疼痛。PID是公认的 沙眼衣原体和淋球菌感染的并发症，但高达70%的病例是 特发性的。细菌性阴道病(BV)和产后出血之间的联系已被认识到，然而很少有研究 检查了与产后应激障碍最相关的特定阴道细菌，尤其是可能 抵制实验室培养。横断面证据表明生殖支原体(MG)和原生动物有关 阴道毛滴虫(TV)是PID的潜在原因，但缺乏前瞻性研究。 我们建议对1199名被认为是性传播高危人群的女性进行前瞻性队列研究 感染者积极随访3年，发展为盆腔炎。我们将开发并应用于样品a 可疑病原体的定量(QPCR)分析小组，包括新发现的BV相关细菌， MG和TV，基于我们的先导研究和大范围16S rRNA基因聚合酶链式反应和下一代测序 以及发现阶段的鸟枪测序。我们将应用NanoStringnCounter炎症面板 以确定特定的炎症基因在子宫内膜样本中是否过度表达 PID患者与无PID患者相比，在细菌种类上具有特异性。我们将互为补充 我们对输卵管和子宫内膜器质性模型的人体研究，使我们能够直接评估 候选病原体与女性上生殖道组织相互作用，引起炎症。我们的 目的是：1)利用广谱的16S rRNA建立一组可用于预测产后出血的候选微生物 高通量测序的基因聚合酶链式反应(细菌)和元基因组鸟枪法测序(所有微生物)； 2)确定我们候选小组中阴道病原体的存在和数量是否相关 使用敏感的定量聚合酶链式反应，以及这些候选病原体在 子宫内膜病变患者的子宫内膜组织与炎性基因信号有关；3)建立模型 4)确定每个病原体引起的细菌感染的群体归因分数(PAF) 在我们的小组中，CT和NG；以及5)确定输卵管内候选PID病原体的炎症潜在性 接种微生物和炎性基因的管状和子宫内膜器质性培养模型 表达被评估。 这将是首次应用最先进的定量聚合酶链式反应分析和阴道微生物组技术对产后出血进行前瞻性研究。 分析，创造发现病原体的可能性，并使人们更好地了解产后出血的病因学。 此外，我们还提出了首次利用输卵管器质和纳米线技术来研究输卵管妊娠的研究。 对非淋球菌、非衣原体病原体的检测并不是常规的，从我们的研究中获得的知识可能 确定新的诊断目标，以优化未来的诊断、预防和治疗 接近了。