Hydrogen Sulfide and Tuberculosis Disease

硫化氢与结核病

• 批准号: 9980777
• 负责人: ADRIE JC STEYN
• 金额: $ 56.66万
• 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: 2018-08-22 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980777
• 关键词: Address; Affect; Binding; Bioenergetics; Biological; Biophysical Process; Biophysics; Carbon Monoxide; Cells; Cessation of life; Chemistry; Citric Acid Cycle; Communicable Diseases; Complex; Data; Development; Diatoms; Disease; Disease Progression; Electron Transport; Energy Metabolism; Enzymes; Epidemic; Flow Cytometry; Gases; Glycolysis; Goals; Growth; Heme Group; Heme Iron; Hibernation; Human; Hydrogen Sulfide; Immune; Immune response; Immunohistochemistry; Infection; Inflammatory Response; Innate Immune Response; Intervention; Mammalian Cell; Mass Spectrum Analysis; Membrane; Metabolic; Metabolic Pathway; Metabolism; Microbe; Mitochondria; Molecular; Mus; Mycobacterium tuberculosis; Myeloid Cells; Natural Immunity; Nitric Oxide; Outcome; Oxidative Phosphorylation; Patients; Pentosephosphate Pathway; Pharmacology; Play; Prevention approach; Preventive Intervention; Pulmonary Tuberculosis; Regulon; Reporting; Research; Resected; Respiration; Role; Signal Transduction; Signaling Molecule; South Africa; Structure of parenchyma of lung; Techniques; Technology; Therapeutic Intervention; Time; Transgenic Organisms; Tuberculosis; Vesicle; animation; base; biological adaptation to stress; biological systems; clinically relevant; cohort; combat; extracellular; fascinate; immunopathology; in vivo; innovation; inorganic phosphate; macrophage; new technology; novel; novel strategies; novel therapeutic intervention; prevent; stable isotope; transcriptome sequencing; tuberculosis treatment

TB remains a global epidemic infecting nearly 2.2 billion people worldwide and causing 1.4 million deaths annually. Understanding the mechanisms of how Mtb enters, maintains and emerges from a dormant state is a vitally important question in the TB field that has not been adequately addressed. New paradigms for how Mtb can persist for decades, and then suddenly reactivate to cause disease, are desperately needed to combat this global epidemic. Recently, hydrogen sulfide (H2S) has been identified as the third endogenously produced gasotransmitter in mammalian cells that is an important cell signalling molecule in numerous biological systems. One of the most exciting biological features of H2S is that it induces a state of “suspended animation”; a hibernation-like metabolic status characterized by a reversible marked reduction of energy expenditure. While H2S has overlapping functions with CO and NO, a role for H2S in Mtb disease progression remains unexplored. Our long-term goal is to dissect new molecular mechanisms that promote Mtb persistence within the host and to use this information to develop novel therapeutic approaches to treat or prevent TB. Our central hypothesis, based upon exciting preliminary data, is that Mtb infection triggers a localized increase of host-generated H2S that (i) induces a state of deeply reduced metabolism to impede an adequate immune response, and (ii) stimulates Mtb respiration and growth, to accelerate death of the host. The rationale of this proposal is that successful completion of our aims will establish a new paradigm for understanding Mtb disease and persistence. Once the mechanisms whereby Mtb persists are known, we anticipate that targeted pharmacological manipulation will result in novel and more effective approaches to the prevention and treatment of TB. We will apply novel techniques such as real-time extracellular metabolic flux analysis and stable isotope analysis of immune cells, transgenic H2S-deficient mice, and freshly resected human TB lung tissue from a well-established patient cohort in Durban, South Africa to accurately describe roles for H2S in the bioenergetics and immunometabolism of TB. The research is innovative, in our opinion, because it represents a substantive departure from the status quo by applying novel technologies and unique patient cohorts to examine the role of H2S in TB for the first time. This contribution is significant because it has the potential to make a lasting, positive change to existing paradigms in TB research, particularly into how the gasotransmitter H2S impacts Mtb energy metabolism and dormancy as well as dysregulation of innate and adaptive immune cells during infection.

结核病仍然是一种全球流行病，感染了全球近22亿人，导致140万人死亡 每年一次。了解结核分枝杆菌如何进入、维持和脱离休眠状态的机制 是结核病领域一个尚未得到充分解决的极其重要的问题。新的范例 结核分枝杆菌如何能持续数十年，然后突然重新激活而导致疾病，这是迫切需要研究的 抗击这一全球流行病。最近，硫化氢(H_2S)被确认为内源性的第三种。 在哺乳动物细胞中产生的气体递质是许多细胞中重要的信号分子 生物系统。硫化氢最令人兴奋的生物特征之一是它会引起一种“悬浮”状态 动感“；一种类似冬眠的新陈代谢状态，其特征是能量可逆地显著减少 支出。虽然硫化氢与一氧化碳和一氧化氮的功能重叠，但硫化氢在结核分枝杆菌疾病进展中的作用 仍未被探索。我们的长期目标是剖析促进结核分枝杆菌的新的分子机制。 在宿主内的持久性，并利用这些信息开发新的治疗方法来治疗或 预防结核病。我们的中心假设是，基于令人兴奋的初步数据，结核分枝杆菌感染引发了 宿主产生的硫化氢的局部增加，(I)导致代谢深度降低的状态，以阻碍 充分的免疫反应，以及(Ii)刺激结核杆菌的呼吸和生长，以加速宿主的死亡。 这项提议的理由是，成功完成我们的目标将建立一个新的范例 了解结核分枝杆菌病和持久力。一旦知道结核分枝杆菌持续存在的机制，我们 预期有针对性的药物操作将导致新的和更有效的方法来治疗 结核病的防治。我们将应用新技术，如实时细胞外代谢流量 转基因H_2S缺陷小鼠和新鲜切除小鼠免疫细胞的分析和稳定同位素分析 从南非德班一位久负盛名的患者队列中提取的人类结核病肺组织准确描述 硫化氢在结核病生物能量学和免疫代谢中的作用。在我们看来，这项研究是创新的， 因为它代表着通过应用新技术和独特的 患者队列首次检查硫化氢在结核病中的作用。这一贡献意义重大，因为它具有 对结核病研究的现有范式进行持久的、积极的改变的潜力，特别是如何 气体递质H_2S影响Mtb能量代谢和休眠以及先天和 感染期间的适应性免疫细胞。