Toxin secretion and trafficking by Mycobacterium tuberculosis

结核分枝杆菌的毒素分泌和运输

• 批准号: 10632980
• 负责人: MICHAEL NIEDERWEIS
• 金额: $ 70.68万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-17 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632980
• 关键词: Address; Antibodies; Apoptosis; Bacteria; Biological Assay; C-terminal; Cell Death; Cells; Complex; Cytosol; Data; ELF3 gene; Elements; Exotoxins; Genes; Grant; Human; Hydrolysis; Hypoxia; Immune response; In Situ; In Vitro; Infection; Lipid Bilayers; Liposomes; Macrophage; Mass Spectrum Analysis; Membrane; Membrane Proteins; Molecular; Molecular Analysis; Molecular Conformation; Mus; Mutate; Mycobacterium tuberculosis; N-terminal; Necrosis; Operon; Pathogenesis; Pathway interactions; Peptide Hydrolases; Permeability; Phagosomes; Phenotype; Play; Pore Proteins; Property; Proteins; Research Project Grants; Resolution; Role; Route; Structure; System; Toxin; Tuberculosis; VDAC1 gene; Virulence; Water; crosslink; cytotoxic; experimental study; in vivo; membrane assembly; microbial; mouse model; mutant; novel; pathogenic bacteria; trafficking; tuberculosis granuloma

Project Summary - Toxin secretion and trafficking by Mycobacterium tuberculosis The ability to control the timing and mode of host cell death plays a pivotal role in microbial infections. Most pathogenic bacteria use toxins to evade and/or subvert immune responses, to survive and replicate in the host. CpnT is an outer membrane protein with an N-terminal channel domain and a C-terminal toxin domain (TNT), which causes necrotic cell death in host cells. Up-to-date TNT is the only known exotoxin of Mycobacterium tuberculosis. We showed that TNT is secreted into the cytosol of macrophages infected with M. tuberculosis where it hydrolyzes NAD+. NAD+ depletion by TNT activates necroptosis, a programmed cell death pathway. Importantly, necroptosis-deficient mice are more resistent to infection with M. tuberculosis, underlining the importance of this pathway for tuberculosis pathogenesis. Permeabilization of the phagosomal membrane is a critical step in the pathogenesis of M. tuberculosis, not only because it required for M. tuberculosis proteins such as the toxin TNT to reach the cytosol of infected cells, but it also enables M. tuberculosis to escape from the phagosome resulting in bacterial dissemination. Thus, TNT secretion and trafficking are an important components of the intracellular survival strategy of M. tuberculosis and for tuberculosis pathogenesis. This research project will reveal novel molecular mechanisms of toxin secretion and trafficking by M. tuberculosis and the role of these mechanisms in virulence and pathogenesis of M. tuberculosis.

项目摘要 - 结核分枝杆菌的毒素分泌和运输 控制宿主细胞死亡时间和模式的能力在微生物感染中起着关键作用。最多 致病细菌利用毒素来逃避和/或破坏免疫反应，以便在宿主体内生存和复制。 CpnT 是一种外膜蛋白，具有 N 端通道结构域和 C 端毒素结构域 (TNT)， 导致宿主细胞坏死性细胞死亡。最新TNT是唯一已知的分枝杆菌外毒素 结核。我们发现 TNT 被分泌到感染结核分枝杆菌的巨噬细胞的胞浆中 它会水解 NAD+。 TNT 消耗 NAD+ 会激活坏死性凋亡，这是一种程序性细胞死亡途径。 重要的是，坏死性凋亡缺陷的小鼠对结核分枝杆菌感染具有更强的抵抗力，这强调了 该途径对于结核病发病机制的重要性。吞噬体膜的透化是 结核分枝杆菌发病机制中的关键步骤，不仅因为它需要结核分枝杆菌蛋白 例如毒素 TNT 可以到达受感染细胞的细胞质，但它也使结核分枝杆菌能够逃脱 吞噬体导致细菌传播。因此，TNT 的分泌和贩运是一个重要的 结核分枝杆菌细胞内生存策略的组成部分和结核病发病机制。这 研究项目将揭示结核分枝杆菌毒素分泌和运输的新分子机制 以及这些机制在结核分枝杆菌毒力和发病机制中的作用。