METABOLIC REPROGRAMMING OF T CELL ENERGY METABOLISM IN TUBERCULOSIS AND HIV

全世界有近17亿人无症状地感染结核分枝杆菌（Mtb）， 结核病的病原体。与艾滋病毒合并感染以及多药耐药（MDR）和广泛耐药的传播， 耐药（XDR）结核分枝杆菌菌株构成了全球公共卫生控制措施的主要障碍。T细胞 衰竭，定义为T细胞功能的恶化，是许多慢性感染的标志， 感染部位存在延长的抗原暴露和炎症信号。然而，很少有 关于这些功能衰竭的细胞和它们的代谢障碍之间的联系， 特别是在人TB/HIV肺的情况下。鉴于免疫激活是严重依赖于能量的， 以及病原体导致新陈代谢不平衡，我们对结核病/艾滋病毒如何 重新编程免疫代谢途径，以及这是否可以通过宿主导向治疗（HDT）逆转， 恢复T细胞代谢。我们的长期目标是了解结核分枝杆菌/艾滋病毒如何扰乱宿主的新陈代谢， 疾病，复活或宿主死亡，以及如何利用这些知识用于治疗目的。 我们的中心假设是Mtb/HIV在人肺中失调T细胞能量代谢，导致肺结核。 抑制局部感染的有效免疫控制，这可以通过HDT恢复。这一假设 是基于基础科学研究者之间不寻常的全球合作努力而制定的， 南非的心胸外科医生和病理学家，以及表观遗传学、蛋白质组学和代谢组学专家 在美国和欧洲。我们的假设是建立在大量的初步数据，这些数据表明， 对新鲜切除的人结核病肺组织进行常规分析的可行性，并显示Mtb对照组与对照组不同， 生物能量通路和免疫检查点。基本原理有几个方面：首先，表型 功能耗竭的T细胞群的表征主要限于动物模型， 到目前为止，还没有研究从新切除的人结核病/艾滋病肺组织中检测这些人群 组织，代表了我们知识中的一个重大翻译空白。其次，检查代谢 人类TB/HIV肺中功能衰竭的T细胞群的需求将使我们能够确定关键的 代谢检查点可能代表HDT的新药理学靶点。更深一层的了解， 代谢检查点参与T细胞耗竭，HDT可能是一种可能的干预策略，以振兴 这些细胞和重振抗结核免疫力。第三，确定营养需求和代谢 促进生产性T细胞应答并阻碍向耗尽的T细胞程序过渡的途径 可以为结核病/艾滋病疫苗设计提供令人兴奋的新基准。这项研究是创新的，因为它 代表了一个新的和实质性的脱离现状，通过应用新的技术和独特的 患者群组以检查人TB肺中的T细胞耗竭。这一贡献意义重大，因为它 突破结核病领域主要障碍的可能性;新切除的结核病肺组织的常规分析。

Close to 1.7 billion people worldwide are asymptomatically infected with Mycobacterium tuberculosis (Mtb), the etiological agent of TB. Co-infection with HIV and the spread of multidrug-resistant (MDR) and extensively drug- resistant (XDR) Mtb strains constitutes a major impediment to worldwide public health control measures. T cell exhaustion, defined as the deterioration of T cell function, is a hallmark of many chronic infections due to prolonged antigen exposure and inflammatory signals present at the site of infection. However, very little is known regarding the link between these functionally exhausted cells and their metabolic insufficiencies, particularly in the context of the human TB/HIV lung. Given that immune activation is critically energy-dependent, and that pathogens cause imbalances in metabolism, there is a gap in our knowledge on how Mtb/HIV reprograms immunometabolic pathways, and whether this can be reversed by host-directed therapy (HDT) to rejuvenate T cell metabolism. Our long-term goal is to understand how Mtb/HIV perturbs host metabolism leading to disease, reactivation, or death of the host, and how this knowledge can be leveraged for therapeutic purposes. Our central hypothesis is that Mtb/HIV dysregulates T cell energy metabolism in the human lung, leading to the suppression of effective immune control of localized infection, which could be restored by HDT. This hypothesis has been formulated based on an unusual global collaborative effort between basic science investigators, cardiothoracic surgeons, and pathologists in South Africa, and epigenetic, proteomic and metabolomic experts in the USA and Europe. Our hypothesis is built upon substantial Preliminary Data which demonstrate the feasibility of routine analyses of freshly resected human TB lung tissue, and show that Mtb controls distinct bioenergetic pathways and immune checkpoints. The rationale is several fold: Firstly, phenotypic characterization of functionally exhausted T cell populations has been largely restricted to animal models, and to date, there have been no studies examining these populations from freshly resected human TB/HIV lung tissue, representing a significant translational gap in our knowledge. Secondly, examining the metabolic requirements of functionally exhausted T cell populations in the human TB/HIV lung will enable us to identify key metabolic checkpoints that may represent novel pharmacological targets for HDT. With greater knowledge of the metabolic checkpoints involved in T cell exhaustion, HDT may be a possible intervention strategy to revitalize these cells and reinvigorate anti-TB immunity. Thirdly, identifying nutritional requirements and metabolic pathways that promote productive T cell responses and hinder the transition towards exhausted T cell programs could provide exciting new benchmarks for TB/HIV vaccine design. The research is innovative, because it represents a new and substantive departure from the status quo by applying novel technologies and unique patient cohorts to examine T cell exhaustion in the human TB lung. This contribution is significant because it has the potential to breach a major barrier in the TB field; routine analysis of freshly resected TB lung tissue.