ULTIMATE

项目摘要/摘要 结核性脑膜炎(TBM)死亡率很高，特别是在感染艾滋病毒的患者中，有一种 迫切需要改善治疗。长期以来，脑内炎症一直被认为是一种重要的 TBM预后的决定因素和辅助抗炎皮质类固醇治疗已被证明 预防未感染艾滋病毒的TBM患者的死亡，但不是残疾。皮质类固醇是唯一的宿主 定向治疗在结核病治疗中被证明是有益的，但其效果不大，其不良反应 数量很大，而且它们降低死亡率的机制尚不清楚。此外，有证据表明 其作用的异质性，取决于脑内炎症的个体差异 反应；以及艾滋病毒感染者是否从皮质类固醇中受益仍不确定。 细胞代谢对免疫细胞的功能至关重要。我们最近发现高浓度的 脑脊液(CSF)色氨酸强烈预测印尼TBM患者的死亡率。利用基因组- 广泛的SNP分析我们确定了11个与两种脑脊液色氨酸相关的数量性状基因座 在单独的患者队列中的浓度和存活率。许多问题仍然存在。色氨酸是怎样的 在TBM过程中代谢发生了变化？它与炎症、免疫病理和对 皮质类固醇?色氨酸代谢是如何受基因调控的？最后，也是非常重要的，什么是 HIV合并感染对TBM治疗前后色氨酸代谢的影响？ 我们的目标是通过整合来自越南和中国的大型研究的数据和样本来解决这些问题 印度尼西亚在荷兰和美国拥有最先进的组学技术和系统生物学。基于 我们之前的研究结果Ultraal的首要目标是确定1500名TBM患者的色氨酸代谢和 300名来自印度尼西亚和越南之前研究的其他脑感染的对照，使用最先进的 LC-MS平台。我们的第二个目标是定义色氨酸代谢的遗传调节在tbm 同一患者组DNA全基因组SNP分型与全基因组测序相结合 一个子集(n=200)。我们的第三个目标是识别预测皮质类固醇效应的生物标记物，并发现 通过将临床和神经放射学数据与脑脊液相结合，为宿主导向治疗提供潜在的新靶点 随机服用皮质类固醇或安慰剂的600名患者的转录组学、代谢组学和宿主基因分型。 我们将在HIV感染和未感染的患者中解决这三个目标，因为HIV相关的TBM具有更高的 死亡率和不同的免疫病理学。 我们强大的初步数据，独特的访问两个大型生物档案和正在进行的随机对照试验 在TBM方面，大规模临床和多层组学数据集成方面的专业知识有望提供 改变对TBM发病机制的认识并发现未来宿主导向的新靶点 治疗。

Project Summary/abstract Tuberculous meningitis (TBM) has a very high mortality, especially in HIV-infected patients, and there is an urgent need to improve treatment. Intracerebral inflammation has long been recognized as an important determinant of TBM outcome and adjunctive anti-inflammatory corticosteroid treatment have been shown to prevent death, but not disability, in HIV-uninfected people with TBM. Corticosteroids represent the only host directed therapy of proven benefit in tuberculosis treatment, yet their effect is modest, their adverse effects substantial, and the mechanism by which they reduce mortality is unknown. Furthermore, there is evidence for heterogeneity in their effect, dependent upon inter-individual variation in the intracerebral inflammatory response; and whether those with HIV-infection benefit from corticosteroids remains uncertain. Cellular metabolism is critical for the function of immune cells. We recently found that high concentrations of cerebrospinal fluid (CSF) tryptophan strongly predicted mortality in Indonesian TBM patients. Using genome- wide SNP analysis we identified 11 quantitative trait loci that were associated with both CSF tryptophan concentrations and survival in a separate patient cohort. Many questions remain. How is tryptophan metabolism altered during TBM? How does it correlate with inflammation, immunopathology, and response to corticosteroids? How is tryptophan metabolism genetically regulated? Lastly, and very importantly, what is the effect of HIV co-infection on tryptophan metabolism before and during TBM treatment? Our aim is to address these questions by integrating data and specimens from large studies in Vietnam and Indonesia with state-of-the-art omics technology and systems biology in the Netherlands and USA. Based on our previous study findings ULTIMATE’s first aim is to define tryptophan metabolism in 1500 TBM patients and 300 controls with other brain infections from previous studies in Indonesia and Vietnam, using state-of-the-art LC-MS platforms. Our second aim is to define the genetic regulation of tryptophan metabolism in TBM with a combination of genome-wide SNP-typing of DNA from the same patient group and whole genome sequencing of a subset (n=200). Our third aim is to identify biomarkers predicting the effect of corticosteroids, and discover potential new targets for host-directed therapy by integrating clinical and neuroradiological data with CSF transcriptomics, metabolomics, and host genotyping of 600 patients randomized to corticosteroids or placebo. We will address these 3 aims in HIV-infected and uninfected patients because HIV-associated TBM has higher mortality and different immunopathology. Our strong preliminary data, unique access to two large bioarchives and on-going randomized controlled trials in TBM, and expertise in integration of large-scale clinical and multi-layer ‘omics’ data promises to provide a step-change in understanding TBM pathogenesis and discovery of new targets for future host-directed therapies.