Immunometabolism of M. tuberculosis/HIV co-infection

结核分枝杆菌/HIV合并感染的免疫代谢

• 批准号: 9294970
• 负责人: ADRIE JC STEYN
• 金额: $ 15.51万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-13 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294970
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Advanced Development; Alpha Cell; Antimycobacterial Agents; Bioenergetics; Biological Assay; Blood Circulation; Cells; Cellular Immunity; Data; Diagnostic; Disease; Energy Metabolism; Etiology; Future; Glucose; Goals; HIV; HIV Infections; HIV/TB; Health; Human; Immune; Immune response; Immunity; Immunologic Markers; Impairment; Individual; Infection; Intervention; Knowledge; Light; Measures; Metabolic; Metabolic Pathway; Metabolism; Mycobacterium bovis; Mycobacterium tuberculosis; Natural Immunity; Observational Study; Oxygen Consumption; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Play; Population; Prevention approach; Preventive Intervention; Public Health; Pulmonary Tuberculosis; Regulation; Reporting; Research; Resected; Respiration; Risk; Role; Shapes; Slice; South Africa; Structure of parenchyma of lung; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tuberculosis; Vaccines; Viral; Work; adaptive immunity; age group; clinically relevant; co-infection; cohort; extracellular; healthy volunteer; human disease; immune function; indexing; innovation; innovative technologies; macrophage; monocyte; new technology; novel; novel diagnostics; pandemic disease; prognostic; prophylactic; prospective; respiratory; stable isotope; targeted treatment; tool; tuberculosis treatment; vaccination against tuberculosis

Close to 1.7 billion people worldwide are asymptomatically infected with Mycobacterium tuberculosis (Mtb), the etiological agent of TB. Furthermore, co-infection with HIV dramatically increases the risk of developing active TB, and constitutes a major impediment to worldwide public health control measures. The only available vaccine, M. bovis BCG, is insufficient at protecting all age groups against the most common presentation of the disease, pulmonary TB. While it is widely recognized that cellular metabolism plays a fundamental role in orchestrating protective (and destructive) immune responses, a significant gap in our knowledge is how Mtb dysregulates host immunometabolism to establish a persistent infection. Our long-term goal is to better understand the mechanisms by which HIV modulates TB latency and how these mechanisms can be manipulated for therapeutic and prophylactic purposes. The objective of this work is to generate a mechanistic understanding of the role of immunometabolism in Mtb and HIV infection. Our central hypothesis is that metabolic reprogramming during Mtb/HIV coinfection drives a dysregulated immune response that promotes lethal pathology in susceptible hosts. This hypothesis has been formulated on the basis of our strong preliminary data derived from novel stable isotope (C13-glucose) incorporation assays using freshly resected human tuberculous lung tissue (“Warburg slices”), which show that Mtb causes a shift in host cell energy metabolism. Secondly, we will apply novel techniques such as real-time metabolic flux analysis to non- invasively measure the oxygen consumption rate, extracellular acidification rate, spare respiratory capacity, maximal respiration, and ATP turnover of cells infected with Mtb and/or HIV. This powerful technology has not yet been applied to study the bioenergetics of bacterial/viral host interaction. Thirdly, this technology has enabled us to demonstrate that the bioenergetic capacity of monocytes isolated from PBMCs in TB patients is dramatically impaired compared to that of healthy volunteers. The rationale is that successful completion of this proposal will (i) establish a new, clinically relevant paradigm of TB/HIV disease that sheds light on dysregulated host immune responses during pathogenesis. This will advance development of new diagnostic tools and host-directed therapies that target metabolism in infected individuals. Secondly, (ii) this proposal will provide a unique diagnostic/prognostic platform to compare a well-established vaccine strain with pathogenic Mtb, which may also provide new parameters to test future vaccine strains and predict candidates that will elicit robust protective immune responses upon Mtb challenge. The research is innovative, in our opinion, because it represents a new and substantive departure from the status quo by applying novel technologies and unique patient cohorts to examine immunometabolism as paradigm to better understand TB/HIV disease. This contribution is significant because it is the first step in the continuum of TB/HIV research that has the potential to make a lasting, positive change to existing paradigms in HIV/TB research.

全球近17亿人不对称感染结核分枝杆菌（MTB）， 结核病的病因学药。此外，与艾滋病毒的共同感染大大增加了积极发展的风险 结核病，这构成了全球公共卫生控制措施的主要障碍。唯一可用的 疫苗M. Bovis BCG不足以保护所有年龄组免受最常见的表现 疾病，肺结核。虽然广泛认识到细胞代谢在 策划保护性（和破坏性）免疫反应，我们所知的一个重大差距是MTB 失调的宿主免疫代谢以建立持续的感染。我们的长期目标是改善 了解HIV调节结核病潜伏期的机制以及这些机制如何 用于治疗和预防性目的。这项工作的目的是生成机械 了解免疫代谢在MTB和HIV感染中的作用。我们的中心假设是 MTB/HIV共感染期间的代谢重编程驱动了促进的免疫激素失调 易感宿主的致命病理。该假设是根据我们的强大提出的 使用新鲜切除的新型同位素（C13-葡萄糖）合并测定的初步数据 人类结核组织（“ Warburg Slices”），这表明MTB会导致宿主细胞能量的变化 代谢。其次，我们将应用新颖的技术，例如实时代谢通量分析 侵入性测量氧气消耗率，细胞外酸化率，备用呼吸能力， 最大呼吸和感染了MTB和/或HIV的细胞的ATP周转。这项强大的技术还没有 然而，应用于研究细菌/病毒宿主相互作用的生物能学。第三，这项技术有 使我们能够证明从TB患者中从PBMC分离的单核细胞的生物能力是 与健康的志愿者相比，龙则受损。理由是成功完成 提案将（i）建立一个与结核病/艾滋病毒疾病的新的，临床上相关的范式，以阐明 发病机理期间的失调宿主免疫反应。这将推动开发新的诊断 靶向感染个体的代谢的工具和宿主定向的疗法。其次，（ii）该提议将 提供一个独特的诊断/预后平台，以将良好的疫苗菌株与致病性进行比较 MTB，这也可能提供新的参数来测试未来的疫苗菌株并预测将引起的候选者 MTB挑战时强大的保护免疫反应。在我们看来，这项研究具有创新性，因为它 通过应用新颖的技术和独特 患者人群将免疫代谢视为范式，以更好地了解结核病/HIV疾病。这 贡献很重要，因为它是结核病/艾滋病毒研究连续性的第一步 为了对HIV/TB研究中现有的范例做出持久的积极改变。