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: 10185506
• 负责人: MICHAEL SHILOH
• 金额: $ 70.77万
• 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/10185506
• 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; 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/antagonist; 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给新宿主的能力。 结核分枝杆菌(Mtb)，人类疾病结核病的病原体，也是最常见的 人类历史上成功的病原体，很可能也使用复杂的手段从一个人传播到 下一步，包括调解干酪化、组织破坏和空中传播。然而，尽管有Mtb的死亡人数 虽然已经对世界健康产生了影响，但导致结核分枝杆菌传播的分子机制仍然难以捉摸。一个 活动性肺结核的主要症状是咳嗽，而咳嗽是主要的传播机制。虽然 咳嗽是结核分枝杆菌雾化和传播的主要途径，目前对其影响因素知之甚少。 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 代表特定血统的基因在人类中更为普遍，但患病率的差异是否源于 细菌传播性及其相关因素如咳嗽和气雾化的差异 细菌是未知的。因此，迫切需要更好地表征结核分枝杆菌的传播动力学 以及咳嗽与传播的关系。因为伤害性神经元介导咳嗽，以及一些细菌 包括分枝杆菌分泌的针对神经元的复杂分子，我们假设结核分枝杆菌产生 触发伤害性神经元的分子，从而激活咳嗽反应，从而促进传递。我们 发现并表征了一种这样的分子的活性，硫脂-1，最近发现了第二种 由强毒分枝杆菌产生的分子。在拟议的研究中，我们将(1)确定和研究 神经元和实验动物中的Sulfolid-1受体，(2)表征第二种伤害性感受器的活性 分子，并确定其活性如何与Sulfolipid-1结合 (3)开发和使用复杂的结核分枝杆菌传播系统来测量传播、咳嗽和雾化 并利用该系统对多种结核分枝杆菌的传播率进行比较 缺乏咳嗽诱导分子的突变体。这项拟议的工作有望确定相关的新因素 具有伤害性神经元激活、咳嗽和分枝杆菌传播。