Toxin-antitoxin systems are important for niche-specific colonization and stress resistance of uropathogenic Escherichia coli.
Toxin-antitoxin systems are important for niche-specific colonization and stress resistance of uropathogenic Escherichia coli.
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DOI：
10.1371/journal.ppat.1002954
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Mulvey MA
中科院分区：
文献类型：
--
作者：
Norton JP;Mulvey MA
毒素-抗毒素（TA）系统普遍存在于许多细菌基因组中，并与生物膜和持久性细胞的形成有关，但个体染色体编码的TA系统在细菌发病过程中的作用尚不清楚。在大肠杆菌编码的已知TA系统中，只有一个子集与肠外致病性大肠杆菌（ExPEC）菌株有关。这些病原体寄生于不同的生态位，是脓毒症、脑膜炎和尿路感染的主要原因。通过小鼠感染模型，我们发现两种TA系统（yemf - yoeb和YbaJ-Hha）分别促进尿路致病菌ExPEC CFT073在膀胱内的定植，而由毒素PasT和抗毒素PasI组成的第三种TA系统对肾脏内ExPEC的存活至关重要。在抗生素存在的情况下，PasTI TA系统还能促进expc持久细胞的形成，并显著提高病原体对营养限制以及氧化和亚硝化胁迫的抵抗力。就其本身而言，低水平表达的PasT可以保护expc免受这些压力，而过表达的PasT则是有毒的，并导致细菌停滞。PasI的过表达可以挽救过去诱导的停滞，表明PasI是一个真正的TA系统。通过诱变，我们发现过去的抗逆性和毒性作用可以解耦并映射到不同的结构域。毒性与PasT的n端序列特异性相关，该区域也促进持久性细胞的发育。这些结果表明，TA相关毒素具有离散的、多用途的功能，并表明单个TA系统可以根据毒素表达水平和特定的环境生态位为细菌提供明显的适应度优势。毒素-抗毒素（TA）系统广泛存在于原核生物中，包括许多重要的人类病原体。长期以来，人们一直假设TA系统有助于细菌发病，但尚未描述与任何单个TA系统相关的明确表型。利用生物信息学，我们证明了TA系统的不同子集与肠道外致病性大肠杆菌（ExPEC）的主要细菌病原体群有关。这些细菌是全世界大多数尿路感染的原因，也是败血症和脑膜炎的主要原因。在小鼠感染模型中，我们发现三种与exp相关的TA系统独立作用，促进细菌在宿主尿路内的生存和持久性。此外，我们发现与这些TA系统之一相关的毒素蛋白增加了exic在抗生素面前的抗逆性和持久性。这项工作证明了特异性TA系统在exic发病机制中的功能重要性，突出了它们作为治疗靶点的潜力。
Toxin-antitoxin (TA) systems are prevalent in many bacterial genomes and have been implicated in biofilm and persister cell formation, but the contribution of individual chromosomally encoded TA systems during bacterial pathogenesis is not well understood. Of the known TA systems encoded by Escherichia coli, only a subset is associated with strains of extraintestinal pathogenic E. coli (ExPEC). These pathogens colonize diverse niches and are a major cause of sepsis, meningitis, and urinary tract infections. Using a murine infection model, we show that two TA systems (YefM-YoeB and YbaJ-Hha) independently promote colonization of the bladder by the reference uropathogenic ExPEC isolate CFT073, while a third TA system comprised of the toxin PasT and the antitoxin PasI is critical to ExPEC survival within the kidneys. The PasTI TA system also enhances ExPEC persister cell formation in the presence of antibiotics and markedly increases pathogen resistance to nutrient limitation as well as oxidative and nitrosative stresses. On its own, low-level expression of PasT protects ExPEC from these stresses, whereas overexpression of PasT is toxic and causes bacterial stasis. PasT-induced stasis can be rescued by overexpression of PasI, indicating that PasTI is a bona fide TA system. By mutagenesis, we find that the stress resistance and toxic effects of PasT can be uncoupled and mapped to distinct domains. Toxicity was specifically linked to sequences within the N-terminus of PasT, a region that also promotes the development of persister cells. These results indicate discrete, multipurpose functions for a TA-associated toxin and demonstrate that individual TA systems can provide bacteria with pronounced fitness advantages dependent on toxin expression levels and the specific environmental niche occupied. Toxin-antitoxin (TA) systems are widespread among prokaryotes, including many important human pathogens. It has long been hypothesized that TA systems contribute to bacterial pathogenesis, but clear-cut phenotypes associated with any individual TA system have not been described. Using bioinformatics, we demonstrate that distinct subsets of TA systems are linked with a major group of bacterial pathogens known as Extraintestinal Pathogenic E. coli (ExPEC). These bacteria are responsible for the majority of urinary tract infections worldwide, and are major causes of sepsis and meningitis. Using murine infection models with a reference uropathogenic ExPEC isolate, we found that three of the ExPEC-associated TA systems act independently to promote bacterial survival and persistence within the host urinary tract. Furthermore, we show that the toxin protein associated with one of these TA systems increases ExPEC stress resistance and persistence in the face of antibiotics. This work demonstrates the functional importance of specific TA systems to ExPEC pathogenesis, highlighting their potential as therapeutic targets.
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