Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution.
Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution.
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DOI：
10.1371/journal.pgen.1000767
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发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
Cox JS
中科院分区：
文献类型：
--
作者：
Ramage HR;Connolly LE;Cox JS
毒素-抗毒素（TA）系统是普遍存在于微生物基因组中的应激反应遗传元件，在人类主要病原体结核分枝杆菌中异常丰富。为什么M。结核病具有如此多的TA系统，它们在病原体的独特生物学中起什么作用尚不清楚。为了解决这些问题，我们已经采取了一个全面的方法来识别和功能特性的所有TA系统编码的M。结核病基因组在这里，我们表明，88个假定的TA系统候选人存在于M。结核病，比以前想象的要多得多。比较基因组分析表明，这些系统中的绝大多数是保守的M。结核复合体（MTBC），但在其他分枝杆菌中基本不存在，包括M.结核我们发现，许多M。结核病TA系统位于可辨别的基因组岛内，因此可能最近通过水平基因转移获得。我们发现了一个新的TA系统位于核心基因组中，在整个属中是保守的，这表明它可能履行所有分枝杆菌共同的作用。通过在M.因此，我们证明了30编码一种功能性毒素及其同源抗毒素。我们发现，毒素的最大的家庭TA系统，VapBC，通过抑制翻译mRNA切割。表达谱分析表明，四个系统在体内可能遇到的应激过程中被特异性激活，包括缺氧和巨噬细胞的吞噬作用。MTBC中TA基因的扩增和维持，加上发现一个子集被应激转录激活，表明TA系统对M.结核病发病机制结核病（TB）仍然是一个主要的全球健康问题，每年造成200万人死亡。结核病发病机制的一个标志是，杆菌可以进入一个缓慢或非生长状态，以响应宿主的免疫系统。由于这些持久存在的细菌对抗生素治疗具有耐药性，因此从人群中消除结核病的努力必须包括针对休眠生物体的治疗，因为它们最终可以恢复复制以引起活动性疾病。结核分枝杆菌，结核病的病原体，如何改变其复制动力学响应宿主的线索还不清楚。毒素-抗毒素（TA）系统，可以控制其他细菌的持久性，在M。结核病，这表明他们是重要的结核病的发病机制。令人惊讶的是，这些众多的TA系统中的绝大多数仅在致病性分枝杆菌中保守，这表明它们的获得在分枝杆菌中是重要的。结核病的演变在88个公认的TA系统中，我们发现30个在分枝杆菌中有功能。这些系统的一个子集被激活后，暴露于感染过程中遇到的压力，表明特定的TA系统参与适应宿主的环境线索。这些基因是开发针对持久性细菌的新疗法的有希望的候选基因。
Toxin-antitoxin (TA) systems, stress-responsive genetic elements ubiquitous in microbial genomes, are unusually abundant in the major human pathogen Mycobacterium tuberculosis. Why M. tuberculosis has so many TA systems and what role they play in the unique biology of the pathogen is unknown. To address these questions, we have taken a comprehensive approach to identify and functionally characterize all the TA systems encoded in the M. tuberculosis genome. Here we show that 88 putative TA system candidates are present in M. tuberculosis, considerably more than previously thought. Comparative genomic analysis revealed that the vast majority of these systems are conserved in the M. tuberculosis complex (MTBC), but largely absent from other mycobacteria, including close relatives of M. tuberculosis. We found that many of the M. tuberculosis TA systems are located within discernable genomic islands and were thus likely acquired recently via horizontal gene transfer. We discovered a novel TA system located in the core genome that is conserved across the genus, suggesting that it may fulfill a role common to all mycobacteria. By expressing each of the putative TA systems in M. smegmatis, we demonstrate that 30 encode a functional toxin and its cognate antitoxin. We show that the toxins of the largest family of TA systems, VapBC, act by inhibiting translation via mRNA cleavage. Expression profiling demonstrated that four systems are specifically activated during stresses likely encountered in vivo, including hypoxia and phagocytosis by macrophages. The expansion and maintenance of TA genes in the MTBC, coupled with the finding that a subset is transcriptionally activated by stress, suggests that TA systems are important for M. tuberculosis pathogenesis. Tuberculosis (TB) continues to be a major global health problem, causing 2 million deaths every year. A hallmark of TB pathogenesis is that the bacilli can enter into a slow or non-growing state in response to the host immune system. Because these persistent bacteria are resistant to antibiotic treatment, efforts to eliminate TB from the human population must include therapies to target dormant organisms as they can eventually resume replication to cause active disease. How Mycobacterium tuberculosis, the causative agent of TB, alters its replication dynamics in response to host cues is not understood. Toxin-antitoxin (TA) systems, which may control persistence in other bacteria, are massively expanded in M. tuberculosis, suggesting that they are important for TB pathogenesis. Surprisingly, the vast majority of these numerous TA systems are conserved only in pathogenic mycobacteria, suggesting their acquisition was important in M. tuberculosis evolution. Of the 88 putative TA systems identified, we show that 30 are functional in mycobacteria. A subset of these systems is activated upon exposure to stresses encountered during infection, indicating that specific TA systems are involved in adapting to environmental cues in the host. These genes are promising candidates for the development of novel therapies to target persistent bacteria.
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影响因子：
3.2
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.251327898
发表时间：
2001-12-04
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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