Biomarkers of Chlamydial Susceptibility and Disease

在一部分感染沙眼衣原体的妇女中，感染逃避免疫控制，上升到 上生殖道。在理解衣原体如何激活通路方面存在一个根本性的空白 感染会导致妇女的免疫病理和生殖疾病。它的继续存在是一个意义重大的 识别生物标志物以诊断或预测暴露后生殖后遗症的风险的障碍。这个 该计划的长期目标是开发减少传播和预防生殖道的疫苗。 暴露于沙眼衣原体后的后遗症。这项提案的总体目标是确定 女性无症状上行性感染和子宫内膜炎及其易感性/风险的遗传生物标志物 疾病。中心假设是STI引起的保护性和免疫病理反应 与特有的转录签名和遗传变异有关。这个项目的基本原理是 识别对上行性感染的易感性和后续免疫病理风险的生物标志物将 通过以下方式加速合理的疫苗设计和测试：(I)确定最有可能受益于 免疫，以促进适当的动力研究，(2)使疫苗试验的群体选择能够平衡， 以及(Iii)作为疫苗疗效的临床衡量标准。血液传播的转录型图谱分析 衣原体生殖道感染的谱系揭示了与疾病相关的特定炎症途径 并启用了诊断无症状感染妇女子宫内膜炎的生物标志物小组的定义 衣原体负担高。在强劲的初步数据指引下，以下三个具体目标将考验 假设：1)确定与衣原体上升呈正相关或负相关的候选生物标志物 无症状妇女的感染；2)确定对上升衣原体易感性的遗传生物标记物 感染和后续生殖后遗症的风险；以及3)确定致病途径及其关键 使用因果网络分析，在衣原体感染上升过程中使用调节器。第一个目标将概述 新队列中局部感染或上尿路受累的妇女的宫颈炎症反应 高度暴露的妇女(TRAC2，核心B)。病原菌载量、合并感染、宫颈阴道菌群和激素 避孕药将被评估为混杂因素或额外的生物标志物。剩下的目标将集中在 通过整合来自TRAC2和先前分析的队列的基因、基因表达和疾病表型 表达数量性状基因座(EQTL)定位和因果中介检验，以及在疾病识别上的应用 因果基因，使用图形模型。在我们看来，提出的研究是创新的，因为它将 实施一种全面、无偏见的方法来识别分子生物标记物 与疾病相关的临床人群。这项拟议的研究具有重要意义，因为它有望翻译成 直接用于人体抗衣原体疫苗的评估，对诊断和治疗具有广泛的重要性 对新疗法的评价。

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.