Role of mycobacterial dynamin-like proteins in the biogenesis of membrane vesicles, and host-pathogen interactions

分枝杆菌动力样蛋白在膜囊泡生物发生和宿主-病原体相互作用中的作用

• 批准号: 10673219
• 负责人: Gloria Marcela Rodriguez
• 金额: $ 20.46万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673219
• 关键词: Affect; Antibiotic Resistance; Antibiotics; Attenuated Vaccines; Bacteria; Biochemical; Biochemistry; Biogenesis; Cell Communication; Cell physiology; Cells; Communication; Complement; Complex; Data; Disease; Dynamin; Environment; Etiology; Eukaryotic Cell; Genetic; Goals; Granulomatous; Host resistance; Human; Immune; Immune response; Immune system; In Vitro; Individual; Infection; Inflammatory; Intervention; Knowledge; Mediating; Membrane; Molecular; Mutation; Mycobacterium tuberculosis; Natural Immunity; Organism; Pathogenesis; Pathologic; Persons; Play; Positioning Attribute; Prevalence; Production; Prokaryotic Cells; Property; Protein Family; Proteins; Public Health; Research; Role; Shapes; Structure; Testing; Tuberculosis; Vesicle; Virulence; Virulence Factors; Work; defense response; experimental study; extracellular; extracellular vesicles; immunoregulation; in vivo; loss of function mutation; macrophage; member; membrane biogenesis; mouse model; mutant; mycobacterial; novel; pathogen; prevent; protein function; resistant strain; success; vesicular release

Despite the widespread use of an attenuated vaccine and several antibiotics, tuberculosis (TB) continues to be a global public health problem. Over 1.2 million people died from TB in 2019. This dire situation is compounded by increasing prevalence of antibiotic resistant strains of Mycobacterium tuberculosis (Mtb), the main etiological agent of human TB. Central to Mtb success is its ability to evade, modulate, and even manipulate host immune defense response. Consequently, bacterial factors involved in undermining the immune system are potentially good targets for TB intervention. Like many other bacteria, Mtb actively produces extracellular vesicles (EVs) in vitro and in vivo. These are membrane enclosed spherical structures that allow the bacteria to concentrate and secrete a variety of molecules, and communicate with other cells in their environment. The release of EVs by Mtb infecting macrophages enables the delivery of pathogenicity factors and immunomodulatory molecules into the host cell, and the extracellular milieu. Strong evidence from in vitro studies indicates that EVs may allow Mtb to remotely influence bystander immune cells. However, the limited understanding of the molecular mechanisms involved in vesicle biogenesis, and the lack of mutants deficient in vesicle production have impeded progress in elucidating the relevance of vesicle secretion to Mtb virulence. Our preliminary work identified the dynamin-like proteins (DLP) of Mtb as essential factors for efficient EVs release and characterized a DLP mutant deficient in vesicle biogenesis. We are now well positioned to dissect DLP's function in vesicle formation and assess the role of EV production during infection, using a mouse model of TB; those are the main goals of this proposal. We anticipate the findings will advance the TB field by highlighting ways to target vesicle release, or disrupt the effects of vesicles in host-resistance to TB.

尽管减毒疫苗和多种抗生素得到广泛使用，但结核病 (TB) 仍然存在 全球公共卫生问题。 2019 年，超过 120 万人死于结核病。这种可怕的情况变得更加复杂 结核分枝杆菌 (Mtb) 抗生素耐药菌株的流行率不断增加， 人类结核病的病原体。 Mtb 成功的核心在于其规避、调节甚至操纵的能力 宿主免疫防御反应。因此，细菌因素会破坏免疫系统 是结核病干预的潜在良好目标。 与许多其他细菌一样，结核分枝杆菌在体外和体内都会积极产生细胞外囊泡 (EV)。这些都是 膜封闭的球形结构，使细菌能够集中并分泌多种 分子，并与其环境中的其他细胞进行通信。 Mtb 感染释放电动汽车 巨噬细胞能够将致病因子和免疫调节分子输送到宿主细胞中， 和细胞外环境。体外研究的有力证据表明，电动汽车可能允许 Mtb 远程 影响旁观者免疫细胞。然而，人们对所涉及的分子机制的了解有限。 在囊泡生物发生中，缺乏囊泡产生缺陷的突变体阻碍了这方面的进展 阐明囊泡分泌与 Mtb 毒力的相关性。我们的初步工作确定了类似动力的 Mtb 蛋白 (DLP) 作为有效 EV 释放的重要因素，并表征了 DLP 突变体缺陷 囊泡生物发生。我们现在已经准备好剖析 DLP 在囊泡形成中的功能并评估 使用结核病小鼠模型观察 EV 产生在感染过程中的作用；这些是本提案的主要目标。 我们预计这些发现将通过强调靶向囊泡释放或扰乱结核病领域的方法来推进结核病领域的发展。 囊泡对宿主抵抗结核病的影响。