The anti-sigma factor TcdC modulates hypervirulence in an epidemic BI/NAP1/027 clinical isolate of Clostridium difficile.
The anti-sigma factor TcdC modulates hypervirulence in an epidemic BI/NAP1/027 clinical isolate of Clostridium difficile.
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DOI：
10.1371/journal.ppat.1002317
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发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Lyras D
中科院分区：
文献类型：
--
作者：
Carter GP;Douce GR;Govind R;Howarth PM;Mackin KE;Spencer J;Buckley AM;Antunes A;Kotsanas D;Jenkin GA;Dupuy B;Rood JI;Lyras D
医院感染越来越被认为是一个主要的患者安全问题。现代医院环境和相关的医疗保健实践为微生物病原体的快速进化提供了一个利基，这些微生物病原体非常适合在这种环境中生存和增殖，之后它们可以感染易感患者。对于诸如耐甲氧西林金黄色葡萄球菌 (MRSA) 和耐万古霉素肠球菌 (VRE) 等细菌病原体来说，情况显然就是如此，这两种病原体都获得了对抗菌药物的耐药性，并且存活率和毒力特性都增强，这给治疗医生带来了严重的治疗困境。最近发现，产芽孢细菌艰难梭菌也属于这一类。自 2000 年以来，全球艰难梭菌医院感染急剧增加，主要是由于流行性或高毒力分离株的出现，这些分离株似乎具有广泛的抗生素耐药性和毒力特性。对于这些菌株的出现、其持久性和毒力的增加，人们提出了各种假设，但缺乏支持性的实验数据。在这里，我们描述了一种使用同基因菌株的遗传方法来识别与艰难梭菌高毒力发展相关的因素。这项研究提供的证据表明，毒素产生的负调节因子抗西格玛因子 TcdC 中自然发生的突变是流行性艰难梭菌分离株产生高毒力的重要因素，可能是因为该突变导致毒素产生显着增加，这是迄今为止有争议的假设。这些结果对艰难梭菌的发病机制和毒力具有重要意义，因为它们表明携带类似突变的菌株具有发展高毒力表型的内在潜力。医院感染越来越被认为是一个主要的患者安全问题，医院环境为微生物病原体的快速进化提供了一个利基，这些微生物病原体非常适合感染易感患者。形成孢子的艰难梭菌就是这样一种细菌，它会导致接受抗生素治疗的患者患病。自 2000 年以来，由于似乎具有扩展的抗生素耐药性和毒力特性的高毒力分离株的出现，艰难梭菌感染急剧增加。在这里，我们使用遗传方法来识别与艰难梭菌高毒力发展相关的因素。这项研究表明，毒素产生的负调节因子抗西格玛因子 TcdC 中自然发生的突变是导致流行分离株产生高毒力的重要因素，可能是因为它导致毒素产生显着增加。这些结果对艰难梭菌发病机制具有重要意义，因为它们表明携带类似突变的菌株具有发展高毒力表型的内在潜力。这项研究增加了我们对这些新变异菌株如何引起疾病以及它们为何危害更大的理解，这对于制定预防和治疗这些感染的改进策略至关重要。
Nosocomial infections are increasingly being recognised as a major patient safety issue. The modern hospital environment and associated health care practices have provided a niche for the rapid evolution of microbial pathogens that are well adapted to surviving and proliferating in this setting, after which they can infect susceptible patients. This is clearly the case for bacterial pathogens such as Methicillin Resistant Staphylococcus aureus (MRSA) and Vancomycin Resistant Enterococcus (VRE) species, both of which have acquired resistance to antimicrobial agents as well as enhanced survival and virulence properties that present serious therapeutic dilemmas for treating physicians. It has recently become apparent that the spore-forming bacterium Clostridium difficile also falls within this category. Since 2000, there has been a striking increase in C. difficile nosocomial infections worldwide, predominantly due to the emergence of epidemic or hypervirulent isolates that appear to possess extended antibiotic resistance and virulence properties. Various hypotheses have been proposed for the emergence of these strains, and for their persistence and increased virulence, but supportive experimental data are lacking. Here we describe a genetic approach using isogenic strains to identify a factor linked to the development of hypervirulence in C. difficile. This study provides evidence that a naturally occurring mutation in a negative regulator of toxin production, the anti-sigma factor TcdC, is an important factor in the development of hypervirulence in epidemic C. difficile isolates, presumably because the mutation leads to significantly increased toxin production, a contentious hypothesis until now. These results have important implications for C. difficile pathogenesis and virulence since they suggest that strains carrying a similar mutation have the inherent potential to develop a hypervirulent phenotype. Hospital infections are increasingly being recognised as a major patient safety issue with the hospital environment providing a niche for the rapid evolution of microbial pathogens that are well adapted to infecting susceptible patients. The spore-forming Clostridium difficile is one such bacterium, which causes disease in patients undergoing antibiotic therapy. Since 2000, there has been a striking increase in C. difficile infections due to the emergence of hypervirulent isolates that appear to possess extended antibiotic resistance and virulence properties. Here we use a genetic approach to identify a factor linked to the development of hypervirulence in C. difficile. This study shows that a naturally occurring mutation in a negative regulator of toxin production, the anti-sigma factor TcdC, is an important factor contributing to the development of hypervirulence in epidemic isolates, presumably because it leads to significantly increased toxin production. These results have important implications for C. difficile pathogenesis since they suggest that strains carrying a similar mutation have the inherent potential to develop a hypervirulent phenotype. This study has increased our understanding of how these new variant strains cause disease and why they are more harmful, which is critical for the development of improved strategies for preventing and treating these infections.
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影响因子：
64.8
作者：
JUST, I;SELZER, J;AKTORIES, K
通讯作者：
AKTORIES, K
影响因子：
3.5
作者：
Braun, V;Hundsberger, T;vonEichelStreiber, C
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DOI：
10.1073/pnas.0914322107
发表时间：
2010-04-20
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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影响因子：
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作者：
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通讯作者：
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