Translational approaches to improve understanding and outcome in Tuberculous meningitis

摘要 当结核分枝杆菌(Mtb)穿过血脑时，就会出现结核性脑膜炎(TBM)。 屏障(BBB)，是最致命和最致命的结核病(TB)形式。在一些患者群体中， 包括HIV患者在内，尽管接受了治疗，TBM的死亡率仍接近50%，长期残疾是非常常见的 在因永久性脑损伤而幸存的人中。这些损伤很大程度上是由组织损伤引起的。 免疫反应和代谢障碍导致神经毒性和退行性神经损害。 这个项目是基于我们的假设，即tbm的不良临床结果是由于组织损伤。 炎症，缺乏适当的治疗方法来抑制适得其反的宿主反应，以及不足 抗生素对中枢神经系统(CNS)损伤的渗透性。 我们提出了一个翻译和临床研究的集成计划，以开发和验证工具， 生物标志物和模型将有助于预测疾病导致的残疾，量化药物在该部位的渗透率 疾病的特征，疾病进展的特征，以及对治疗的模型反应。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 兔TBM模型的发病机制、疾病部位的药物渗透和新治疗方法的测试 疾病。临床组学签名不仅将产生死亡和残疾的预测因子，而且还将指导 兔模型的优化。该项目将从两个单独资助的IIA阶段和III阶段试验中提取资金 (分别为激光-TBM和强-TBM)在南非，评估增强的安全性和有效性 抗菌和宿主导向治疗，包括批准用于结核病的抗生素(大剂量利福平添加到 治疗标准)和重新调整用途的药物(利奈唑胺和阿司匹林)，用于成人TBM。我们将使用优化的 兔TBM模型测定结核特异性抗生素和重组抗生素对中枢神经系统损伤的穿透性 新奇的特工。如果证明有足够的中枢神经系统穿透，这些病毒的病原体和宿主定向活性 药物将在兔模型中进一步评估。使用这些输出，我们将构建一个翻译模型 整合临床和兔的发病部位PK-PD数据以确定治疗干预的贡献 关于临床试验的疗效终点，并确定用于TBM抗结核治疗的PK-PD靶点。结果是 这些综合方法中的一种将被向前翻译，以提出循证药物治疗方案， 提高死亡率和神经功能障碍的潜力。首席调查员和他们的团队联合起来 四个机构的基础、翻译和临床研究，具有多组学分析、药理学方面的专业知识 和免疫生物学。

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.