INTERCEPT

项目概要/摘要 脑膜炎（TBM）通常影响幼儿，免疫病理学可能有助于 高死亡率和身体及认知的发病率。最近的无偏交叉组学研究已经确定 参与成年人TBM结果的生物学途径，可以帮助开发更有效的宿主， 目前还不清楚类似或其他途径是否与儿童期TBM有关。 我们以前发现高水平的脑脊液（CSF）色氨酸，营养分枝杆菌 结核病和预测CSF色氨酸浓度的遗传性状作为死亡率的强标志物， TBM通过整合大规模的临床、代谢组学和基因组学数据， 并确定了与成年患者中TBM结果有关的其他代谢途径。另外，我们 发现CSF中基质金属蛋白酶（MMP-10）的水平，以及与CSF相关的遗传特征， MMP-10水平也可预测成年TBM患者的死亡率。这表明金属蛋白酶也可能是 可能通过血脑屏障功能障碍导致脑水肿， 炎症细胞的涌入。这些发现提出了一个问题，如果这些生物途径也参与了 免疫病理学和儿童TBM的不良结局。最后，我们最近发现， 可能会减少脑梗死和成年人因TBM死亡。因此，我们正在进行一项单独资助的 阿司匹林治疗儿童结核性脑膜炎的3期临床试验，以确定它是否能降低死亡率和长期残疾。 因此，基于我们先前的工作，我们假设：包括色氨酸在内的特定代谢途径 代谢影响儿科TBM的结果，这是遗传调节的（目标1）; 金属蛋白酶与TBM的免疫病理学和结局有关（目的2）; 大规模临床和“组学”数据以及儿童和成人TBM患者的比较可以预测 阿司匹林的治疗效果，并确定儿童TBM的宿主定向治疗的新靶点（目的3）。测试 基于这些假设，我们将联合收割机结合全球最大的一些TBM临床研究的独特访问， 在整合多组学和深度表型分析数据方面拥有卓越的专业知识。 我们强大的初步数据，访问两个大型生物档案，从成人TBM，一个正在进行的随机对照 儿科TBM试验，以及大规模临床和多层“组学”数据整合方面的专业知识， 为理解儿童TBM发病机制和发现未来的新靶点提供了一个步骤 宿主导向疗法。

Project Summary/abstract Tuberculous meningitis (TBM) disproportionally affects small children, and immunopathology likely contributes to its high mortality and physical and cognitive morbidity. Recent unbiased cross-omics studies have identified biological pathways involved in the outcome of TBM in adults that could help development of more effective host- directed therapy for TBM, but it is unknown if similar or other pathways are implicated in childhood TBM. We previously identified high levels of cerebrospinal fluid (CSF) tryptophan, a nutrient for Mycobacterium tuberculosis, and genetic traits that predict CSF tryptophan concentrations as strong markers for mortality of TBM. By integrating large-scale clinical, metabolomics and genomics data we have strengthened these findings and identified additional metabolic pathways implicated in outcome of TBM in adult patients. Separately, we found that CSF levels of matrix metalloproteinases (MMP-10), as well as genetic traits associated with CSF MMP-10 levels, also predict mortality of adult TBM patients. This suggests that metalloproteinases may also be implicated in TBM outcome, possibly through blood-brain barrier dysfunction resulting in cerebral edema and influx of inflammatory cells. These findings raise the question if these biological pathways are also involved in the immunopathology and poor outcome of pediatric TBM. Lastly, we recently showed that adjunctive aspirin might reduce brain infarctions and death from TBM in adults. Therefore, we are conducting a separately funded phase 3 clinical trial of aspirin in children with TBM to determine if it reduces mortality and long-term disability. Therefore, based on our previous work we hypothesize that: specific metabolic pathways including tryptophan metabolism influence outcome of pediatric TBM, and that this is genetically regulated (Aim 1); metalloproteinases are implicated in the immunopathology and outcome of TBM (Aim 2); and integration of large-scale clinical and ‘omics’ data and comparison of pediatric and adult TBM patients can predict the therapeutic effect of aspirin, and identify novel targets for host-directed therapy of pediatric TBM (Aim 3). To test these hypotheses, we will combine unique access to some of the largest clinical studies in TBM globally with exceptional expertise in integration of multi-omics and deep-phenotyping data. Our strong preliminary data, access to two large bioarchives from adult TBM, an on-going randomized controlled trial in pediatric TBM, and expertise in integration of large-scale clinical and multi-layer ‘omics’ data promises to provide a step-change in understanding childhood TBM pathogenesis and discovery of new targets for future host-directed therapies.