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都取决于其繁殖和传播到新宿主的能力。 结核分枝杆菌（MTB），人类疾病结核病的致病药物，也是最多的。 人类历史上成功的病原体，也可能采用复杂的手段来从一个人传播到 下一个，包括介导静脉曲张，组织破坏和空中传播。然而，尽管有收费 已经采取了世界卫生的健康，导致MTB传播的分子机制仍然难以捉摸。一个 主动结核病的主要症状是咳嗽，咳嗽是传播的主要机制。虽然 咳嗽是MTB的气化和传播的主要途径，对这些因素知之甚少 在感染期间产生咳嗽。此外，流行病学研究表明MTB菌株 代表特定的谱系在人类中更为普遍，但是患病率的差异是否是由于 细菌传递性和相关因素的差异，例如咳嗽诱导和雾化 细菌是未知的。因此，迫切需要更好地表征MTB的传输动力学 以及咳嗽与传播的关系。因为伤害性神经元介导咳嗽和一些细菌 包括分枝杆菌分泌靶向神经元的复合物分子，我们假设MTB会产生 分子触发伤害性神经元激活咳嗽反应，从而促进传播。我们 发现并表征了一个这样的分子硫脂脂1的活性，并最近确定了第二个分子 由毒性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硫酸1受体，（2）表征第二个伤害感受的活性 神经元和实验动物中的分子，并确定其活性与硫脂脂1的活性结合 （3）开发和使用复杂的MTB传输系统来测量传输，咳嗽和雾化 安全和定量的颗粒，并使用系统比较多种MTB的可传播性 缺乏咳嗽分子的突变体。提议的工作有望确定相关的新因素 具有伤害性神经元激活，咳嗽和分枝杆菌的传播。