Transcriptional and Physiological Changes during Mycobacterium tuberculosis Reactivation from Non-replicating Persistence.
Transcriptional and Physiological Changes during Mycobacterium tuberculosis Reactivation from Non-replicating Persistence.
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DOI：
10.3389/fmicb.2016.01346
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发表时间：
2016
影响因子：
5.2
通讯作者：
Shi L
中科院分区：
文献类型：
--
作者：
Du P;Sohaskey CD;Shi L
结核分枝杆菌可以在宿主的恶劣环境中以不复制或缓慢复制的状态持续数年。虽然活动性疾病主要是由潜伏感染的再激活引起的，但结核分枝杆菌再激活的分子机制仍然知之甚少。我们描述了结核分枝杆菌在缺氧诱导的非复制持久性再激活过程中的生理学和全球转录组学特征。我们发现结核分枝杆菌在再生时的再激活与一个滞后期有关，在这个滞后期，细胞生理和代谢功能的恢复先于细胞复制的恢复。转录组动力学的富集分析揭示了许多代谢途径和转录调控/子网络的变化，这些通路和转录调控/子网络协调了为细胞分裂做准备的代谢和生理转化。特别是，我们发现结核分枝杆菌再生滞后期与持续相关调控/子网络的下调有关，包括DosR、MprA、SigH、SigE和ClgR，以及代谢途径，包括那些参与脂质摄取及其分解代谢的途径。更重要的是，我们发现了一些上调的转录调控和代谢途径，包括与金属运输和再动员、第二信使介导的反应、DNA修复和重组以及主要细胞壁成分合成有关的转录调控和代谢途径。我们还发现，主要替代sigma因子SigE或SigH的失活破坏了持久性的退出，强调了结核分枝杆菌再激活过程中全局转录重编程的重要性。我们的观察结果表明，结核分枝杆菌迟滞期与全球基因表达重编程有关，该重编程定义了重新激活过程的启动。
Mycobacterium tuberculosis can persist for years in the hostile environment of the host in a non-replicating or slowly replicating state. While active disease predominantly results from reactivation of a latent infection, the molecular mechanisms of M. tuberculosis reactivation are still poorly understood. We characterized the physiology and global transcriptomic profiles of M. tuberculosis during reactivation from hypoxia-induced non-replicating persistence. We found that M. tuberculosis reactivation upon reaeration was associated with a lag phase, in which the recovery of cellular physiological and metabolic functions preceded the resumption of cell replication. Enrichment analysis of the transcriptomic dynamics revealed changes to many metabolic pathways and transcription regulons/subnetworks that orchestrated the metabolic and physiological transformation in preparation for cell division. In particular, we found that M. tuberculosis reaeration lag phase is associated with down-regulation of persistence-associated regulons/subnetworks, including DosR, MprA, SigH, SigE, and ClgR, as well as metabolic pathways including those involved in the uptake of lipids and their catabolism. More importantly, we identified a number of up-regulated transcription regulons and metabolic pathways, including those involved in metal transport and remobilization, second messenger-mediated responses, DNA repair and recombination, and synthesis of major cell wall components. We also found that inactivation of the major alternative sigma factors SigE or SigH disrupted exit from persistence, underscoring the importance of the global transcriptional reprogramming during M. tuberculosis reactivation. Our observations suggest that M. tuberculosis lag phase is associated with a global gene expression reprogramming that defines the initiation of a reactivation process.
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影响因子：
2.1
作者：
Gamulin, V;Cetkovic, H;Ahel, I
通讯作者：
Ahel, I
影响因子：
64.5
作者：
Boshoff, HIM;Reed, MB;Mizrahi, V
通讯作者：
Mizrahi, V
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3.6
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Gold, B;Rodriguez, GM;Smith, I
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Smith, I
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3.2
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Zahrt, Thomas C.
影响因子：
11.3
作者：
Becker KW;Skaar EP
通讯作者：
Skaar EP