Project 3: Mechanisms of cough in M. tuberculosis transmission

项目3：咳嗽在结核分枝杆菌传播中的机制

• 批准号: 10190651
• 负责人: MICHAEL SHILOH
• 金额: $ 51.74万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-13 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10190651
• 关键词: Aerosols; Animal Model; Animals; Bacteria; Binding; Biochemical Genetics; Biochemistry; Biological Assay; Biological Models; CRISPR/Cas technology; Carbon Dioxide; Cavia; Cholera Toxin; Collaborations; Complex; Coughing; Data; Desiccation; Diarrhea; Disease; Electrophysiology (science); Foundations; Future; G-Protein-Coupled Receptors; Genes; Genetic; Genus Mycobacterium; Glycolipids; Goals; Human; Immunohistochemistry; Individual; Infection; Knock-out; Laboratories; Lipids; Liquid substance; Measures; Mediating; Mediation; Metabolic Pathway; Modeling; Molecular; Molecular Biology; Mycobacterium tuberculosis; Nebulizer; Neurons; Neurosciences; Nociception; Orphan; Pain; Particle Size; Persons; Phenols; Population; Predictive Factor; Prevalence; Production; Proteins; Recording of previous events; Research; Resistance; Resuscitation; Route; Stress; Symptoms; System; Testing; Tissues; Tuberculosis; Vibrio cholerae; Virulence; Virulent; Work; World Health; aerosolized; disease transmission; epidemiology study; genetic approach; glycolipid receptor; human disease; in vivo; inhibitor/antagonist; insight; mutant; mycobacterial; novel; novel strategies; particle; pathogen; pathogenic bacteria; polyketide synthase; programs; protein complex; receptor; response; screening; success; sulfolipids; sulfotransferase; transmission process

Project Summary/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 or other factors predicted to impact transmission. The proposed work is expected to identify novel factors associated with nociceptive neuron activation, cough and mycobacterial transmission.

项目概要/摘要 任何细菌病原体的成功最终取决于其繁殖和传播给新宿主的能力。 结核分枝杆菌（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，很可能也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，尽管山地车造成了伤亡 尽管结核病已经影响了世界健康，但导致结核分枝杆菌传播的分子机制仍然难以捉摸。一个 活动性结核病的主要症状是咳嗽，而咳嗽是主要的传播途径。虽然 咳嗽是结核分枝杆菌雾化和传播的主要途径，但人们对咳嗽的影响因素知之甚少。 感染时产生咳嗽。此外，流行病学研究表明，Mtb 菌株 代表特定谱系的疾病在人类中更为普遍，但患病率的差异是否是由于 细菌传播性和相关因素（例如咳嗽诱导和雾化）的差异 细菌未知。因此，迫切需要更好地表征 Mtb 的传播动态 以及咳嗽与传播的关系。因为伤害性神经元介导咳嗽，并且一些细菌 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 分子触发伤害性神经元激活咳嗽反应，从而促进传播。我们 发现并表征了一种此类分子 sulfolipid-1 的活性，最近还发现了第二种分子 由剧毒分枝杆菌产生的分子。在拟议的研究中，我们将 (1) 识别并研究 神经元和实验动物中的sulfolid-1受体，（2）表征第二伤害感受的活性 神经元和实验动物中的分子，并确定其活性如何与 sulfolipid-1 结合 (3) 开发并使用先进的 Mtb 传播系统来测量传播、咳嗽和雾化 安全定量地检测颗粒物，并使用该系统比较各种 Mtb 的传播能力 缺乏咳嗽诱导分子或其他预计影响传播的因素的突变体。拟议的 预计工作将确定与伤害性神经元激活、咳嗽和 分枝杆菌传播。