Biomarkers of Chlamydial Susceptibility and Disease

衣原体敏感性和疾病的生物标志物

• 批准号: 10392975
• 负责人: CATHERINE MARY O'CONNELL
• 金额: $ 33.74万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392975
• 关键词: 16S ribosomal RNA sequencing; Acute; Automobile Driving; Biological Markers; Blood; Cervical; Cervix Uteri; Characteristics; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Clinical; Contraceptive Usage; DNA; Data; Diagnosis; Diagnostic Sensitivity; Disease; Disease Pathway; Ectopic Pregnancy; Endometritis; Evaluation; Exposure to; Focal Infection; Gene Chips; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Markers; Genotype; Goals; High Risk Woman; Human; Immune; Immune response; Immunity; Immunization; Individual; Infection; Infertility; Inflammatory; Inflammatory Response; Knowledge; Lead; Link; Measures; Mediation; Messenger RNA; Modeling; Molecular; Monitor; North Carolina; Oral Contraceptives; Outcome; Participant; Pathology; Pathway Analysis; Pathway interactions; Pelvic Inflammatory Disease; Population; Predisposition; Prevention; Preventive vaccine; Process; Quantitative Trait Loci; Reproductive Health; Research; Research Design; Resolution; Risk; SNP array; Source; Surrogate Endpoint; Testing; Translating; Treatment Efficacy; United States National Institutes of Health; Universities; Vaccine Design; Vaccines; Woman; Women' s Health; Work; adaptive immune response; biomarker identification; biomarker panel; candidate marker; causal variant; cervicovaginal microbiome; chlamydia vaccine; chronic pelvic pain; clinically relevant; co-infection; cohort; cost; diagnosis evaluation; disease phenotype; disorder risk; genome-wide; hormonal contraception; improved; infection risk; innovation; long-term sequelae; molecular marker; novel therapeutics; pathogen; prevent; programs; recruit; reproductive; reproductive morbidity; reproductive tract; response; transcriptomics; transmission process; vaccine development; vaccine efficacy; vaccine evaluation; vaccine trial; vaginal microbiota; working group

In a subset of Chlamydia trachomatis-infected women, the infection escapes immune control and ascends to the upper reproductive tract. There is a fundamental gap in understanding how pathways activated by chlamydial infection lead to immune pathology and reproductive morbidity in women. Its continued existence is a significant barrier to identification of biomarkers to diagnose or predict risk for reproductive sequelae after exposure. The long-term goal of this program is to develop vaccines that reduce transmission and prevent reproductive tract sequelae after exposure to C. trachomatis. The overall objective of this proposal is to identify biomarkers of asymptomatic ascending infection and endometritis in women and genetic biomarkers of susceptibility/risk for disease. The central hypothesis is that protective and immunopathologic responses elicited in response to STI associate with characteristic transcriptional signatures and genetic variance. The rationale for this project is that identifying biomarkers of susceptibility to ascending infection and risk for subsequent immune pathology will accelerate rational vaccine design and testing by (i) identifying individuals most likely to benefit from immunization, to facilitate appropriately powered studies, (ii) enabling balanced group selection for vaccine trials, and (iii) serving as clinical measures of vaccine efficacy. Blood-borne transcriptional profiling of women with a spectrum of chlamydial genital tract infection revealed specific inflammatory pathways associated with disease and enabled definition of a biomarker panel that diagnoses endometritis in asymptomatically-infected women with high chlamydial burden. Guided by strong preliminary data, the following three specific aims will test the hypothesis: 1) Determine candidate biomarkers positively- or negatively associated with ascending chlamydial infection in asymptomatic women; 2) Identify genetic biomarkers of susceptibility to ascending chlamydial infection and risk for subsequent reproductive sequelae; and 3) Identify disease-causing pathways and their key regulators engaged during ascending chlamydial infection, using causal network analysis. The first aim will profile cervical inflammatory responses from women with local infection or upper tract involvement in a new cohort of highly-exposed women (TRAC2, Core B). Pathogen load, co-infection, cervicovaginal microbiome and hormonal contraceptives will be assessed as confounders or additional biomarkers. The remaining aims will focus on integrating genotype, gene expression and disease phenotypes from TRAC2 and previously-profiled cohorts via expression quantitative trait locus (eQTL) mapping and causal mediation test, and on identification of disease- causal genes, using graphical models. The research proposed is innovative, in our opinion, because it will implement a comprehensive, non-biased approach to the identification of molecular biomarkers in a highly disease-relevant clinical population. The proposed research is significant because it is expected to translate directly to anti-chlamydial vaccine evaluation in humans and to have broad importance for diagnosis and for evaluation of novel therapeutics.

在一部分感染沙眼衣原体的女性中，感染逃脱了免疫控制并上升到 上生殖道。对于衣原体如何激活途径的理解存在根本性的差距 感染导致女性免疫病理和生殖发病。它的持续存在具有重要意义 鉴定生物标志物以诊断或预测暴露后生殖后遗症风险的障碍。这 该计划的长期目标是开发减少传播和预防生殖道感染的疫苗 接触沙眼衣原体后的后遗症。该提案的总体目标是确定生物标志物 女性无症状上行感染和子宫内膜炎以及易感性/风险的遗传生物标志物 疾病。中心假设是对性传播感染引起的保护性和免疫病理学反应 与特征转录特征和遗传变异相关。该项目的理由是 识别上行感染易感性的生物标志物和随后免疫病理学的风险将 通过（i）确定最有可能受益的个体，加速合理的疫苗设计和测试 免疫，以促进适当动力的研究，(ii) 为疫苗试验实现平衡的群体选择， (iii) 作为疫苗功效的临床衡量标准。患有以下疾病的女性的血源性转录谱分析 衣原体生殖道感染谱揭示了与疾病相关的特定炎症途径 并定义了一个生物标志物组，用于诊断无症状感染女性的子宫内膜炎 衣原体负荷高。在强有力的初步数据的指导下，以下三个具体目标将检验 假设：1) 确定与上升衣原体呈正相关或负相关的候选生物标志物 无症状女性感染； 2) 鉴定对上行衣原体易感性的遗传生物标志物 感染和随后生殖后遗症的风险； 3) 确定致病途径及其关键 使用因果网络分析，监管机构在衣原体感染上升期间参与其中。第一个目标将简介 在新的队列中，局部感染或上呼吸道受累的女性的宫颈炎症反应 高度暴露的女性（TRAC2，核心 B）。病原体负荷、合并感染、宫颈阴道微生物群和激素 避孕药具将作为混杂因素或额外的生物标志物进行评估。其余目标将集中于 通过整合来自 TRAC2 和之前分析的队列的基因型、基因表达和疾病表型 表达数量性状基因座（eQTL）作图和因果中介测试，以及疾病鉴定 因果基因，使用图形模型。我们认为，所提出的研究具有创新性，因为它将 实施全面、无偏见的方法来高度鉴定分子生物标志物 疾病相关的临床人群。拟议的研究意义重大，因为它有望转化为 直接用于人类抗衣原体疫苗评估，并对诊断和治疗具有广泛的重要性 新疗法的评估。