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Hydrogen Sulfide and Tuberculosis Disease

硫化氢与结核病

基本信息

批准号：
10219117
负责人：
ADRIE JC STEYN
金额：
$ 47.52万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-22 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219117
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 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 preventive intervention stable isotope transcriptome sequencing tuberculosis treatment

项目摘要

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，造成140万人死亡每年。了解Mtb如何进入，维持和从休眠状态出现的机制是结核病领域一个至关重要的问题，但尚未得到充分解决。新的范例，结核病如何能持续几十年，然后突然重新激活引起疾病，迫切需要抗击这一全球流行病。近年来，硫化氢（H2S）被确定为第三大内源性污染物在哺乳动物细胞中产生的气体递质是许多细胞中重要的细胞信号分子，生物系统。H2S最令人兴奋的生物学特征之一是它诱导一种“悬浮”状态，一种类似冬眠的代谢状态，特征是能量的可逆性显著减少支出虽然H2S与CO和NO具有重叠的功能，但H2S在Mtb疾病进展中的作用仍然未被探索。我们的长期目标是剖析促进结核分枝杆菌的新分子机制并利用这些信息开发新的治疗方法来治疗或预防结核病。基于令人兴奋的初步数据，我们的中心假设是，结核分枝杆菌感染引发了一种新的免疫反应。宿主产生的H2S的局部增加，（i）诱导代谢深度降低的状态，以阻碍足够的免疫应答，和（ii）刺激Mtb呼吸和生长，以加速宿主的死亡。提出这一建议的理由是，成功地实现我们的目标将建立一个新的模式，了解结核病及其持续性。一旦了解了结核分枝杆菌持续存在的机制，我们预期靶向药理学操作将导致新的和更有效的方法，预防和治疗结核病。我们将应用新的技术，如实时细胞外代谢通量分析和稳定同位素分析的免疫细胞，转基因H2S缺陷小鼠，和新鲜切除的来自南非德班的一个完善的患者队列的人TB肺组织，以准确描述 H2S在结核病的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，因为它通过应用新技术和独特的技术，患者队列研究H2S在结核病中的作用。这一贡献意义重大，因为它对现有结核病研究范式进行持久、积极变革的潜力，特别是如何气体递质H2S影响Mtb的能量代谢和休眠，以及先天和适应性免疫细胞感染。