Mechanisms of cough in Mycobacterium tuberculosis transmission

咳嗽在结核分枝杆菌传播中的机制

• 批准号: 10368154
• 负责人: MICHAEL SHILOH
• 金额: $ 72.59万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-08 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368154
• 关键词: Aerosols; Animal Model; Animals; Bacteria; Binding; Biochemical Genetics; Biochemistry; Biological; Biological Assay; Biological Models; CRISPR/Cas technology; Cavia; Cells; Cholera Toxin; Complex; Coughing; Data; Diarrhea; Disease; Electrophysiology (science); Foundations; Future; G-Protein-Coupled Receptors; Genes; Genetic; Genus Mycobacterium; Glycolipids; Goals; Human; Immunohistochemistry; Individual; Infection; Knock-out; Laboratories; Lipids; Measures; Mediating; Mediation; Modeling; Molecular; Molecular Biology; Mycobacterium tuberculosis; Nebulizer; Neurons; Nociception; Nociceptors; Orphan; Pain; Persons; Phenols; Population; Prevalence; Production; Proteins; Recording of previous events; Research; Route; Signal Transduction; Symptoms; System; Techniques; Testing; Tissues; Tuberculosis; Vibrio cholerae; Virulence; Virulent; Work; World Health; aerosolized; disease transmission; epidemiology study; genetic approach; glycolipid receptor; human disease; in vivo; inhibitor; insight; mutant; mycobacterial; novel; particle; pathogen; pathogenic bacteria; polyketide synthase; protein complex; receptor; response; screening; success; sulfolipids; sulfotransferase; transmission process

Project Abstract The success of any bacterial pathogen ultimately depends on its ability to multiply and transmit to new hosts. Mycobacterium tuberculosis (Mtb), the causative agent of the human disease tuberculosis and one of the most successful pathogens in human history, likely also employs sophisticated means to spread from one person to the next, including mediating caseation, tissue destruction, and airborne transmission. Yet, despite the toll Mtb has taken on world health, the molecular mechanisms responsible for Mtb transmission remain elusive. A major symptom of active tuberculosis is cough, and cough is a major mechanism of transmission. Although cough is a major route of aerosolization and transmission of Mtb, very little is known about the factors that produce cough during infection. Furthermore, epidemiologic studies have demonstrated that Mtb strains representing specific lineages are more prevalent in humans but whether differences in prevalence are due to differences in bacterial transmissibility and associated factors such as cough induction and aerosolization of bacteria is unknown. Thus, there is an urgent need to better characterize the transmission dynamics of Mtb and the relationship of cough to transmission. Because nociceptive neurons mediate cough, and some bacteria including mycobacteria secrete complex molecules targeting neurons, we hypothesized that Mtb produces molecules to trigger nociceptive neurons to activate the cough response, thereby facilitating transmission. We discovered and characterized the activity of one such molecule, sulfolipid-1, and recently identified a second molecule produced by virulent mycobacteria. In the proposed research we will (1) Identify and study the sulfolid-1 receptor in neurons and experimental animals, (2) Characterize the activity of the second nociceptive molecule in neurons and experimental animals, and determine how its activity combines with that of sulfolipid-1 (3) Develop and use a sophisticated Mtb transmission system to measure transmission, cough and aerosolized particles safely and quantitatively and use the system to compare the transmissibility of a variety of Mtb mutants lacking cough-inducing molecules. The proposed work is expected to identify novel factors associated with nociceptive neuron activation, cough and mycobacterial transmission.

项目摘要 任何细菌病原体的成功最终取决于其繁殖和传播到新宿主的能力。 结核分枝杆菌（Mycobacterium tuberculosis，Mtb）是人类结核病的病原体，也是最常见的结核病之一。 人类历史上成功的病原体，也可能采用复杂的手段从一个人传播到另一个人。 其次，包括介导干酪化、组织破坏和空气传播。然而，尽管Mtb付出了代价， 尽管结核病已成为世界卫生的一个重要问题，但负责结核病传播的分子机制仍然难以捉摸。一 活动性结核病的主要症状是咳嗽，而咳嗽是主要的传播机制。虽然 咳嗽是Mtb雾化和传播的一个主要途径，但人们对Mtb雾化和传播的因素知之甚少。 在感染期间产生咳嗽。此外，流行病学研究表明，结核分枝杆菌菌株 代表特定谱系的基因在人类中更普遍，但流行率的差异是否是由于 细菌传播性的差异和相关因素，如咳嗽诱导和雾化， 细菌未知。因此，迫切需要更好地表征结核病的传播动力学 以及咳嗽与传播的关系。因为伤害感受神经元介导咳嗽， 包括分枝杆菌分泌针对神经元的复杂分子，我们假设Mtb产生 分子来触发伤害感受神经元激活咳嗽反应，从而促进传输。我们 发现并鉴定了一种这样的分子--硫脂-1的活性，最近又鉴定了第二种 由毒性分枝杆菌产生的分子。在拟议的研究中，我们将（1）识别和研究 sulfolid-1受体在神经元和实验动物中的表达，（2）表征第二伤害性感受的活性 分子在神经元和实验动物，并确定如何结合其活动与硫脂-1 (3)开发和使用先进的结核病传播系统，以测量传播、咳嗽和雾化 颗粒安全和定量，并使用该系统来比较各种Mtb的传输率 缺乏咳嗽诱导分子的突变体。这项拟议的工作预计将确定新的因素， 与伤害性神经元激活、咳嗽和分枝杆菌传播有关。