Sigma Factor SigB Is Crucial to Mediate Staphylococcus aureus Adaptation during Chronic Infections.
Sigma Factor SigB Is Crucial to Mediate Staphylococcus aureus Adaptation during Chronic Infections.
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DOI：
10.1371/journal.ppat.1004870
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发表时间：
2015-04
期刊：
影响因子：
6.7
通讯作者：
Löffler B
中科院分区：
文献类型：
--
作者：
Tuchscherr L;Bischoff M;Lattar SM;Noto Llana M;Pförtner H;Niemann S;Geraci J;Van de Vyver H;Fraunholz MJ;Cheung AL;Herrmann M;Völker U;Sordelli DO;Peters G;Löffler B
金黄色葡萄球菌是一种主要的人类病原体，可引起从急性侵入性到慢性和难以治疗的一系列感染。金黄色葡萄球菌感染是细菌宿主细胞入侵以及细菌动态改变表型的能力，从侵袭性野生型变为小菌落变体（SCV），后者适合细胞内长期持续存在。细菌转换和适应机制的潜在机制似乎非常动态，但在很大程度上是未知的。在这里，我们分析了全局S的作用和串扰。通过产生单、双和三重突变体，并在不同的体外和体内感染模型中用蛋白质组分析测试它们，研究金黄色葡萄球菌调节剂agr、sarA和SigB。我们能够证明SigB是慢性感染适应的关键因素。在急性感染期间，细菌需要agr和sarA基因座的同时作用，以通过引起炎症和细胞毒性来防御入侵的免疫细胞，并逃离其宿主细胞中的吞噬体，使其能够在高细菌密度下解决感染。为了在细胞内持续存在，细菌随后需要沉默agr和sarA。事实上，agr和sarA缺失突变体表达的毒力因子的数量要少得多，并且可以在细胞内持续大量存在。SigB在促进细菌细胞内持久性方面起着至关重要的作用。事实上，Δ sigB突变体不产生SCV，并且在几天内被宿主细胞完全清除。在这项研究中，我们将SigB鉴定为一种重要因子，使细菌能够从解决急性感染的高度侵袭性表型转换为允许长期细胞内持久性的沉默SCV表型。因此，SigB操纵子代表了开发针对慢性和治疗难治性感染的预防和治疗策略的可能靶标。 金黄色葡萄球菌是严重侵袭性感染的常见病原体，可发展为慢性并且变得极其难以根除。慢性感染与改变的细菌表型高度相关，即，小菌落变异体（SCV）在细菌宿主细胞侵入后动态出现，并且高度适应于细胞内的长期持久性。在本研究中，我们通过研究全局S.金黄色葡萄球菌调节因子agr、sarA和SigB。我们证明了这些因素之间的紧密串扰支持细菌在感染的任何阶段，SigB是细菌在长期持续适应的关键因素。在急性期，细菌需要活性agr和sarA系统来诱导炎症和细胞毒性，并在高细菌数量下建立感染。在感染的慢性阶段，SigB下调侵袭性细菌表型并介导动态SCV表型的形成。因此，我们将SigB描述为细菌适应和持久性的关键因素，这代表了针对慢性感染的治疗干预的可能目标。
Staphylococcus aureus is a major human pathogen that causes a range of infections from acute invasive to chronic and difficult-to-treat. Infection strategies associated with persisting S. aureus infections are bacterial host cell invasion and the bacterial ability to dynamically change phenotypes from the aggressive wild-type to small colony variants (SCVs), which are adapted for intracellular long-term persistence. The underlying mechanisms of the bacterial switching and adaptation mechanisms appear to be very dynamic, but are largely unknown. Here, we analyzed the role and the crosstalk of the global S. aureus regulators agr, sarA and SigB by generating single, double and triple mutants, and testing them with proteome analysis and in different in vitro and in vivo infection models. We were able to demonstrate that SigB is the crucial factor for adaptation in chronic infections. During acute infection, the bacteria require the simultaneous action of the agr and sarA loci to defend against invading immune cells by causing inflammation and cytotoxicity and to escape from phagosomes in their host cells that enable them to settle an infection at high bacterial density. To persist intracellularly the bacteria subsequently need to silence agr and sarA. Indeed agr and sarA deletion mutants expressed a much lower number of virulence factors and could persist at high numbers intracellularly. SigB plays a crucial function to promote bacterial intracellular persistence. In fact, ΔsigB-mutants did not generate SCVs and were completely cleared by the host cells within a few days. In this study we identified SigB as an essential factor that enables the bacteria to switch from the highly aggressive phenotype that settles an acute infection to a silent SCV-phenotype that allows for long-term intracellular persistence. Consequently, the SigB-operon represents a possible target to develop preventive and therapeutic strategies against chronic and therapy-refractory infections. Staphylococcus aureus is a frequent pathogen of severe invasive infections that can develop into chronicity and become extremely difficult to eradicate. Chronic infections have been highly associated with altered bacterial phenotypes, i.e., the small colony variants (SCVs) that dynamically appear after bacterial host cell invasion and are highly adapted for intracellular long-term persistence. In this study, we analyzed the underlying mechanisms of the bacterial switching and adaptation process by investigating the functions of the global S. aureus regulators agr, sarA and SigB. We demonstrate that a tight crosstalk between these factors supports the bacteria at any stage of the infection and that SigB is the crucial factor for bacterial adaptation during long-term persistence. In the acute phase, the bacteria require active agr and sarA systems to induce inflammation and cytotoxicity, and to establish an infection at high bacterial numbers. In the chronic stage of infection, SigB downregulates the aggressive bacterial phenotype and mediates the formation of dynamic SCV-phenotypes. Consequently, we describe SigB as a crucial factor for bacterial adaptation and persistence, which represents a possible target for therapeutic interventions against chronic infections.
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影响因子：
3.1
作者：
Beenken, KE;Blevins, JS;Smeltzer, MS
通讯作者：
Smeltzer, MS
影响因子：
3.1
作者：
Ahmed, S;Meghji, S;Nair, SP
通讯作者：
Nair, SP
影响因子：
3.2
作者：
Bayer, MG;Heinrichs, JH;Cheung, AL
通讯作者：
Cheung, AL
影响因子：
3.2
作者：
CHEUNG, AL;YING, P
通讯作者：
YING, P
DOI：
10.1016/j.biocel.2007.10.032
发表时间：
2008-01-01
影响因子：
4
作者：
Cheung, Ambrose L.;Nishina, Koren A.;Tamber, Sandeep
通讯作者：
Tamber, Sandeep