INTERCEPT

项目摘要/摘要 结核性脑膜炎(TBM)对儿童的影响不成比例，免疫病理学可能起到了一定作用 它的高死亡率以及身体和认知的发病率。最近不偏不倚的交叉组学研究发现 参与成人创伤性脑损伤转归的生物学途径，可帮助发展更有效的宿主- 针对TBM的定向治疗，但尚不清楚类似或其他途径是否与儿童TBM有关。 我们先前发现脑脊液中含有高水平的色氨酸，这是分枝杆菌的一种营养物质。 结核病和预测脑脊液色氨酸浓度的遗传特征作为死亡的强烈标志 TBM。通过整合大规模的临床、代谢组学和基因组学数据，我们强化了这些发现 并确定了与成人患者的TBM结局有关的其他代谢途径。另外，我们 研究发现，脑脊液中基质金属蛋白酶(MMP-10)水平以及遗传性状与脑脊液有关 基质金属蛋白酶-10水平也可以预测成人结缔组织病患者的死亡率。这表明，金属蛋白酶可能也是 可能通过血脑屏障功能障碍导致脑水肿和 炎性细胞大量涌入。这些发现提出了一个问题，即这些生物通路是否也参与了 儿童TBM的免疫病理与预后不良。最后，我们最近展示了辅助性阿司匹林 可能会减少成人的脑梗塞和脑血栓形成的死亡。因此，我们正在进行一项单独资助的 阿司匹林在儿童TBM中的3期临床试验，以确定它是否降低了死亡率和长期残疾。 因此，基于我们之前的工作，我们假设：包括色氨酸在内的特定代谢途径 代谢影响儿童TBM的预后，这是受基因调控的(目标1)； 金属蛋白酶与TBM的免疫病理和预后有关(AIM 2)； 大规模的临床和组学数据以及儿童和成人TBM患者的比较可以预测 阿司匹林的疗效，并为儿童TBM的宿主导向治疗寻找新的靶点(目标3)。为了测试 这些假设，我们将把对全球最大规模的TBM临床研究的独特访问与 在整合多组学和深度表型数据方面拥有卓越的专业知识。 我们强大的初步数据，获取了两个来自成人TBM的大型生物档案，正在进行的随机对照 在儿科TBM中的试验，以及大规模临床和多层组学数据集成方面的专业知识，有望 为理解儿童TBM的发病机制和发现未来的新靶点提供了一个阶段性的改变 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.