METABOLIC REPROGRAMMING OF T CELL ENERGY METABOLISM IN TUBERCULOSIS AND HIV

结核病和艾滋病毒中 T 细胞能量代谢的代谢重编程

• 批准号: 10373022
• 负责人: ADRIE JC STEYN
• 金额: $ 48.6万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373022
• 关键词: Affect; Anatomy; Animal Model; Antigens; Antitubercular Agents; Award; Basic Science; Benchmarking; Bioenergetics; CD8-Positive T-Lymphocytes; Capillary Electrophoresis; Carbon Isotopes; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Data; Dependence; Deterioration; Disease; Energy Metabolism; Environment; Epigenetic Process; Etiology; Europe; Evaluation; Flow Cytometry; Focal Infection; Funding; Goals; Granuloma; HIV; HIV/TB; Health; Hospitals; Human; Hypoxia; Immune; Immune response; Immunohistochemistry; Infection; Inflammatory; Intervention; Knowledge; Lesion; Link; Liquid substance; Lung; Mass Fragmentography; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metformin; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Nutrient; Nutrient availability; Nutritional; Nutritional Requirements; Operative Surgical Procedures; Pathologist; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Phenotype; Population; Preparation; Production; Productivity; Proteins; Proteomics; Public Health; Pulmonary Tuberculosis; Refractory; Rejuvenation; Reporting; Research; Research Personnel; Resected; Series; Signal Pathway; Signal Transduction; Site; Slice; South Africa; Structure of parenchyma of lung; Surgeon; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Transcript; Vaccine Design; chronic infection; co-infection; cohort; cytokine; effector T cell; exhaust; exhaustion; experimental study; extensive drug resistance; extracellular; flexibility; guinea pig model; human model; immune activation; immune checkpoint; immune checkpoint blockade; improved; innovation; innovative technologies; lung lesion; metabolomics; new technology; novel; pathogen; pharmacologic; preclinical study; programmed cell death protein 1; programs; prophylactic; small molecule; stable isotope; synergism; targeted treatment; transcriptome sequencing; tuberculosis immunity

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.

全球近17亿人无症状地感染了结核分枝杆菌(Mtb)， 结核病的病原体。与艾滋病毒合并感染和多药耐药(MDR)的传播以及广泛的药物耐药- 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 精疲力竭，定义为T细胞功能的恶化，是许多慢性感染的特征，原因是 感染部位存在长时间的抗原暴露和炎症信号。然而，很少有 已知这些功能耗尽的细胞与它们的代谢不足之间的联系， 特别是在人类结核病/艾滋病毒肺部的情况下。鉴于免疫激活在很大程度上依赖能量， 病原体导致新陈代谢失衡，我们对结核分枝杆菌/艾滋病毒如何 重新编程免疫代谢途径，以及宿主定向治疗(HDT)是否可以逆转这一点 恢复T细胞新陈代谢。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 对于宿主的疾病、重新激活或死亡，以及如何将这些知识用于治疗目的。 我们的中心假设是结核分枝杆菌/艾滋病毒导致人类肺内T细胞能量代谢失调，导致 抑制局部感染的有效免疫控制，可通过HDT恢复。这一假设 是基于基础科学研究人员之间不同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、蛋白质组和代谢学专家 在美国和欧洲。我们的假设建立在大量初步数据的基础上，这些数据表明 对新鲜切除的人肺组织进行常规分析的可行性，并表明结核分枝杆菌控制明显 生物能量途径和免疫检查站。理由有以下几个方面：第一，表型 功能耗尽的T细胞群体的特征在很大程度上局限于动物模型，并且 到目前为止，还没有研究从新切除的人类结核病/艾滋病病毒肺中检测这些人群。 组织，代表着我们知识中的一个显著的翻译鸿沟。第二，检查新陈代谢 人类结核病/HIV肺中功能耗尽的T细胞群的需求将使我们能够识别关键 代谢检查点，可能代表HDT的新药理靶点。有了更多关于 代谢检查点参与T细胞衰竭，HDT可能是一种可能的重振旗鼓的干预策略 这些细胞和重振抗结核病的免疫力。第三，确定营养需求和新陈代谢 促进生产性T细胞反应和阻碍向耗尽的T细胞程序过渡的途径 可以为结核病/艾滋病毒疫苗设计提供令人兴奋的新基准。这项研究具有创新性，因为它 代表着对现状的新的实质性的偏离，通过应用新的技术和独特的 患者队列检查人类肺结核肺中T细胞的耗竭。这一贡献意义重大，因为它具有 突破结核病领域主要障碍的可能性；对新切除的结核病肺组织进行常规分析。

项目成果

Mycobacterium tuberculosis induces decelerated bioenergetic metabolism in human macrophages.

• DOI: 10.7554/elife.39169
• 发表时间: 2018-11-16
• 期刊: eLife
• 影响因子: 7.7
• 作者: Cumming BM;Addicott KW;Adamson JH;Steyn AJ
• 通讯作者: Steyn AJ

LiLA: lipid lung-based ATLAS built through a comprehensive workflow designed for an accurate lipid annotation.

• DOI: 10.1038/s42003-023-05680-7
• 发表时间: 2024-01-05
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Requena, Belen Fernandez;Nadeem, Sajid;Reddy, Vineel P.;Naidoo, Vanessa;Glasgow, Joel N.;Steyn, Adrie J. C.;Barbas, Coral;Gonzalez-Riano, Carolina
• 通讯作者: Gonzalez-Riano, Carolina