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: 10668432
• 负责人: DAVID Neal FREDRICKS
• 金额: $ 78.17万
• 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/10668432
• 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; Growth; 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; Ovarian; Patients; Pelvic Inflammatory Disease; Phase; Pilot Projects; Population; Population Attributable Risks; Postpartum Period; Prevention strategy; Preventive; 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; case control; chronic pelvic pain; clinical practice; cohort; comparison control; 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：Haggerty，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，往往导致不孕症，慢性盆腔疼痛和复发性PID。PID是公认的 沙眼衣原体和淋病奈瑟菌感染的并发症，但高达70%的病例是 特发性的细菌性阴道病（BV）和PID之间的关联是公认的，但很少有研究 检查了与PID最相关的特定阴道细菌，特别关注可能 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 阴道毛滴虫（TV）是PID的潜在病因，但缺乏前瞻性研究。 我们提出了一项前瞻性队列研究，包括1,199名被认为是性传播疾病高风险的妇女。 感染者积极随访三年，以了解PID的发展情况。我们将开发并应用于样品， 可疑病原体的一组定量（qPCR）检测，包括新鉴定的BV相关细菌， MG和TV基于我们的初步研究和宽范围16 S rRNA基因PCR与下一代测序 和鸟枪测序技术我们将NanoString nCounter炎症面板应用于 子宫内膜样本，以确定特定的炎症基因是否在来自子宫内膜的样本中过表达。 PID妇女与非PID妇女相比，在细菌物种特异性的方式。我们将补充 我们对输卵管和子宫内膜类器官模型的人类研究，使我们能够直接评估如何 候选病原体与女性上生殖道的组织相互作用以诱导炎症。我们 目的是：1）开发一组候选微生物，用于使用宽范围16 S rRNA预测PID 基因PCR与高通量测序（细菌）和宏基因组鸟枪测序（所有微生物）; 2)确定我们的候选组中阴道病原体的存在和数量是否与 使用敏感的qPCR检测事件PID，以及这些候选病原体是否存在于 子宫内膜组织与PID患者的炎症基因特征相关; 3）建立模型 4）确定各病原体引起PID的群体归因分数（PAF） 在我们的小组中，CT和NG;和5）确定候选PID病原体在输卵管中的炎症潜力 试管和子宫内膜类器官培养模型，其中接种微生物和炎性基因 表达被评估。 这将是第一项应用最先进的qPCR检测和阴道微生物组的PID前瞻性研究 分析，创造病原体发现的潜力，并赋予PID病因学更好的理解。 此外，我们提出了第一项使用输卵管类器官和NanoString技术研究PID的研究。 非淋球菌、非衣原体病原体的检测不是常规的，从我们的研究中获得的知识可能 确定PID的新诊断靶点，以优化未来的诊断，预防和治疗 接近。

项目成果

Vaginal bacteria elicit acute inflammatory response in fallopian tube organoids: a model for pelvic inflammatory disease.

阴道细菌在输卵管类器官中引起急性炎症反应：盆腔炎的模型。

• DOI: 10.21203/rs.3.rs-2891189/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Yu,Bo;McCartney,Stephen;Strenk,Susan;Valint,Daniel;Liu,Congzhou;Haggerty,Catherine;Fredricks,DavidN
• 通讯作者: Fredricks,DavidN