Inhibition of apoptosis by Rv2456c through Nuclear factor-κB extends the survival of Mycobacterium tuberculosis.
Inhibition of apoptosis by Rv2456c through Nuclear factor-κB extends the survival of Mycobacterium tuberculosis.
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DOI：
10.1016/j.ijmyco.2016.06.018
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发表时间：
2016-12
影响因子：
1.2
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Jurcic Smith KL;Lee S
结核分枝杆菌是结核病的病原体，是一种细胞内病原体，具有多种旨在破坏宿主免疫系统的生存机制。细胞凋亡已被证明具有杀分枝杆菌作用，可激活 CD8+ T 细胞，并受分枝杆菌蛋白的调节。由于迄今为止很少有分枝杆菌蛋白直接参与结核分枝杆菌与宿主细胞凋亡之间的相互作用，因此我们筛选了结核分枝杆菌H37Rv转座子突变体，以鉴定无法抑制细胞死亡（FID）的突变体。其中一种 FID 突变体 FID19 在 Rv2456c 中插入了转座子，对于宿主细胞的生存非常重要。该蛋白的缺乏导致 caspase-3 介导的细胞凋亡增强，这可能是由于无法激活核因子-κB 所致。此外，FID19感染增强了多功能CD8+ T细胞，并在小鼠模型中诱导了更高频率的干扰素-γ分泌免疫细胞。综上所述，我们的数据表明，Rv2456c 通过防止受感染细胞凋亡来抑制宿主的先天性和最终适应性免疫反应，对 H37Rv 的生存很重要。更好地了解宿主与分枝杆菌的相互作用可能有利于开发新的药物靶点和设计更有效的结核病疫苗株。
Mycobacterium tuberculosis, the causative agent of tuberculosis, is an intracellular pathogen with several survival mechanisms aimed at subverting the host immune system. Apoptosis has been shown to be mycobactericidal, to activate CD8+ T cells, and to be modulated by mycobacterial proteins. Since few mycobacterial proteins have so far been directly implicated in the interactions between M. tuberculosis and host cell apoptosis, we screened M. tuberculosis H37Rv transposon mutants to identify mutants that fail to inhibit cell death (FID). One of these FID mutants, FID19, had a transposon insertion in Rv2456c and is important for survival in host cells. The lack of the protein resulted in enhanced caspase-3 mediated apoptosis, which is probably due to an inability to activate nuclear factor-κB. Additionally, FID19 infection enhanced polyfunctional CD8+ T cells and induced a higher frequency of interferon-γ secreting immune cells in a murine model. Taken together, our data suggest that Rv2456c is important for the survival of H37Rv by subduing the innate and ultimately adaptive immune responses of its host by preventing apoptosis of the infected cell. Better understanding of the host-mycobacterial interactions may be beneficial to develop novel drug targets and engineer more efficacious vaccine strains against tuberculosis.