Hydrogen Sulfide and Tuberculosis Disease

硫化氢与结核病

基本信息

批准号：
9767657
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
项目类别：
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/9767657
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

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性流行病，感染全球近 22 亿人，造成 140 万人死亡每年了解 Mtb 如何进入、维持和摆脱休眠状态的机制。是结核病领域的一个至关重要的问题，但尚未得到充分解决。结核分枝杆菌如何能够持续数十年，然后突然重新激活导致疾病，我们迫切需要了解最近，硫化氢（H2S）被确定为第三种内源性污染物。在哺乳动物细胞中产生气体递质，这是许多细胞中重要的细胞信号分子 H2S 最令人兴奋的生物学特征之一是它会诱导一种“悬浮状态”。动画”；类似冬眠的代谢状态，其特征是可逆的能量显着减少虽然 H2S 与 CO 和 NO 具有重叠的功能，但 H2S 在 Mtb 疾病进展中发挥着作用。我们的长期目标是剖析促进 Mtb 的新分子机制。宿主体内的持久性，并利用这些信息来开发新的治疗方法来治疗或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会引发结核病。宿主产生的 H2S 局部增加，(i) 诱导新陈代谢深度降低的状态，以阻碍足够的免疫反应，以及（ii）刺激结核分枝杆菌的呼吸和生长，以加速宿主的死亡。该提案的基本原理是，成功完成我们的目标将为了解 Mtb 疾病和持久性后，我们就可以了解 Mtb 持续存在的机制。预计有针对性的药理学操作将产生新颖且更有效的方法我们将应用实时细胞外代谢通量等新技术。对免疫细胞、转基因 H2S 缺陷小鼠和新鲜切除的小鼠进行分析和稳定同位素分析来自南非德班成熟患者队列的人类结核病肺组织，可准确描述 H2S 在结核病生物能学和免疫代谢中的作用我们认为这项研究具有创新性。因为它代表着通过应用新技术和独特的技术与现状的实质性背离首次研究了 H2S 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现有范式做出持久、积极改变的潜力，特别是如何气体递质 H2S 影响结核分枝杆菌的能量代谢和休眠以及先天和感染期间的适应性免疫细胞。