Translational approaches to improve understanding and outcome in Tuberculous meningitis

摘要 结核分枝杆菌（Mtb）穿过血脑时会引起脑膜炎（TBM） 结核病是最致命和最致残的结核病形式。在一些患者群体中， 包括HIV患者在内，尽管进行了治疗，但TBM死亡率仍接近50%，长期残疾非常常见 在幸存者中造成永久性脑损伤这些损伤很大程度上是由组织损伤引起的 免疫反应和代谢紊乱导致神经毒性和退行性神经损伤。 该项目基于我们的假设，即TBM的不良临床结局是由于组织损伤 炎症，缺乏抑制适得其反的宿主反应的适当治疗，以及 抗生素渗入中枢神经系统（CNS）病变。 我们提出了一个转化和临床研究的综合计划，以开发和验证工具， 生物标志物和模型，这将有助于预测疾病引起的残疾，量化药物渗透的网站 疾病的特征，表征疾病进展，并模拟对治疗的反应。该计划结合了多个- 临床试验样本的组学、药代动力学和药物相互作用分析， 发病机制，疾病部位的药物渗透，以及在兔TBM模型中测试新治疗方法 疾病临床组学特征不仅可以预测死亡和残疾， 兔模型的优化。该项目将借鉴两个单独资助的第IIA期和第III期试验 （分别为LASER-TBM和INTENSE-TBM）在南非进行，评估增强型 抗微生物和宿主导向治疗，包括批准用于结核病的抗生素（高剂量利福平加到 标准治疗）和再利用药物（利奈唑胺和阿司匹林）。我们将使用优化的 兔TBM模型，以测量TB特异性和再利用抗生素的CNS病变渗透， 新型药剂如果证明有足够的中枢神经系统渗透，这些药物的病原体和宿主导向活性 将在兔模型中进一步评价药物。使用这些输出，我们将构建一个平移模型 整合临床和兔疾病部位PK-PD数据，以确定治疗干预的贡献 在临床试验中的疗效终点，并确定结核分枝杆菌的抗结核治疗的PK-PD目标。结果 这些综合方法将被向前转化，以提出基于证据的药物治疗方案， 改善死亡率和神经残疾的潜力。主要调查人员和他们的团队联合收割机 在四个机构进行基础、转化和临床研究，具有多组学分析、药理学和生物医学方面的专业知识。 免疫生物学。

ABSTRACT Tuberculous meningitis (TBM) arises when Mycobacterium tuberculosis (Mtb) crosses the blood-brain barrier (BBB), and is the most lethal and disabling form of tuberculosis (TB). In some patient populations, including HIV patients, TBM mortality approaches 50% despite therapy, and long-term disability is very common amongst survivors due to permanent brain injuries. These injuries are induced in large part by tissue damaging immune responses and by metabolic disturbance leading to neurotoxic and degenerative neurological damage. This project is based on our hypothesis that poor clinical outcomes in TBM are due to tissue damaging inflammation, the lack of adequate therapies that dampen counterproductive host responses, and inadequate antibiotic penetration into central nervous system (CNS) lesions. We propose an integrated program of translational and clinical research to develop and validate tools, biomarkers and models, which will help predict disease-induced disability, quantify drug penetration at the site of disease, characterize disease progression, and model response to therapy. The program combines multi- omic, pharmacokinetic and drug-drug interaction analyses of clinical trial samples, with investigations of pathogenesis, drug penetration at the site of disease, and testing of novel treatments in a rabbit model of TBM disease. The clinical -omics signatures will not only generate predictors of death and disability, but also guide optimization of the rabbit model. The project will draw from two separately funded Phase IIA and Phase III trials (LASER-TBM and INTENSE-TBM, respectively) in South Africa, evaluating the safety and efficacy of enhanced antimicrobial and host-directed therapy, including antibiotics approved for TB (high dose rifampicin added to standard of care) and repurposed drugs (linezolid and aspirin), for adults with TBM. We will use the optimized rabbit model of TBM to measure the CNS lesion penetration of TB-specific and repurposed antibiotics and of novel agents. If adequate CNS penetration is demonstrated, the pathogen- and host-directed activity of these drugs will be further evaluated in the rabbit model. Using these outputs, we will build a translational model integrating clinical and rabbit site-of-disease PK-PD data to define the contribution of therapeutic interventions on efficacy endpoints in clinical trials, and to define PK-PD targets for antitubercular therapy in TBM. The results of these integrated approaches will be forward-translated to propose evidence-based drug regimens with the potential to improve on death rate and neuro-disability. The principal investigators and their teams combine basic, translational and clinical research at four institutions with expertise in multi-omics analyses, pharmacology and immunobiology.