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.

结核病仍然是全球流行病，全球近22亿人，造成140万人死亡再一次。了解MTB进入，保持和从休眠状态出现的机制在结核病领域中，这是一个至关重要的问题，尚未得到充分解决。新的范式 MTB如何持续数十年，然后突然重新激活以引起疾病，迫切需要打击这种全球流行病。最近，硫化氢（H2S）已被确定为第三在哺乳动物细胞中产生的高递质，这是许多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了“悬挂状态” 动画”；一种类似冬眠的代谢状态，其特征是可逆的能量减少支出。虽然H2S与CO和NO具有重叠的功能，但H2在MTB疾病进展中的作用仍然出乎意料。我们的长期目标是剖析促进MTB的新分子机制主机内的持久性并使用此信息来开发新颖的治疗方法来治疗或防止结核病。基于令人兴奋的初步数据，我们的中心假设是MTB感染会触发A 宿主生成的H2S的局部增加，（i）影响了一种大大降低新陈代谢的状态足够的免疫反应，（ii）刺激MTB呼吸和生长，以加速宿主死亡。该提议的理由是，成功完成我们的目标将为了解MTB疾病和持久性。一旦已知MTB的机制，我们就可以预计有针对性的药理学操纵将导致新颖，更有效的方法结核病的预防和治疗。我们将应用新颖的技术，例如实时细胞外代谢通量免疫细胞，转基因H2S缺乏小鼠和新鲜切除的分析和稳定的同位素分析来自南非德班的良好患者队列的人类TB肺组织以准确描述 H2在结核病的生物能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颖的技术和独特的方式代表了与现状的实质性不同患者首次检查H2S在TB中的作用。这项贡献很重要，因为它具有在结核病研究中对现有范式做出持久，积极改变的潜力，尤其是增发剂H2S影响MTB能量代谢和休眠以及先天和感染过程中自适应免疫细胞。