Toxin secretion and trafficking by Mycobacterium tuberculosis

项目摘要-结核分枝杆菌的毒素分泌和运输 控制宿主细胞死亡的时间和模式的能力在微生物感染中起着关键作用。最 病原菌利用毒素逃避和/或破坏免疫反应，在宿主中存活和复制。 CpnT是具有N-末端通道结构域和C-末端毒素结构域（TNT）的外膜蛋白， 导致宿主细胞的坏死性细胞死亡。最新的TNT是唯一已知的分枝杆菌外毒素 结核我们发现，TNT分泌到巨噬细胞感染M。结核 在那里它水解NAD+。由TNT引起的NAD+消耗激活坏死性凋亡，这是一种程序性细胞死亡途径。 重要的是，坏死性凋亡缺陷小鼠对M.结核病，强调 这一途径对结核病发病的重要性。吞噬体膜的透化作用是一种 是M.结核病，不仅因为它需要M.结核蛋白 如毒素TNT到达受感染细胞的胞质溶胶，但它也使M.肺结核逃避 吞噬体导致细菌传播。因此，TNT的分泌和运输是一个重要的 的细胞内生存策略的组成部分。结核病和结核病的发病机制。这 该研究项目将揭示M.结核 以及这些机制在M.结核

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.