Genome Plasticity of agr-Defective Staphylococcus aureus during Clinical Infection.
Genome Plasticity of agr-Defective Staphylococcus aureus during Clinical Infection.
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DOI：
10.1128/iai.00331-18
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发表时间：
2018-10
影响因子：
3.1
通讯作者：
van Bakel H
中科院分区：
文献类型：
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作者：
Altman DR;Sullivan MJ;Chacko KI;Balasubramanian D;Pak TR;Sause WE;Kumar K;Sebra R;Deikus G;Attie O;Rose H;Lewis M;Fulmer Y;Bashir A;Kasarskis A;Schadt EE;Richardson AR;Torres VJ;Shopsin B;van Bakel H
金黄色葡萄球菌引起的菌血症的治疗通常是无效的，即使根据实验方案的治疗条件是最佳的。适应的亚克隆，如那些携带突变，减弱agr介导的毒力激活，与持续感染和患者死亡率。金黄色葡萄球菌引起的菌血症的治疗通常是无效的，即使根据实验方案的治疗条件是最佳的。适应的亚克隆，如那些携带突变，减弱agr介导的毒力激活，与持续感染和患者死亡率。为了鉴定agr缺陷突变体中的其他改变，我们对来自几个感染了沙门氏菌的病人的定植和感染部位的克隆对进行了全基因组测序和组装。金黄色葡萄球菌表现出AGR功能的宿主内丧失。我们报告与agr失活相关的事件导致agr缺陷的血液和鼻孔菌株对，与野生型对照组相比，这些菌株对富含突变。来自同一患者的定植菌株和感染菌株之间以及来自不同患者的菌株之间突变的随机分布表明，agr缺陷菌株的遗传复杂性大部分来自长期感染或治疗诱导的应激。然而，在其中一个agr缺陷型感染菌株中，多重遗传变化导致了血液感染小鼠模型中毒力的增加，绕过了agr突变，并提高了某些变化被选择的可能性。表达谱相关的agr缺陷突变体的毒性升高，恢复表达agr调节ESAT6样VII型分泌系统，一个已知的毒力因子。因此，agr基因座外的其他突变可能有助于在S.金黄色葡萄球菌AGR突变体与患者预后不良相关。
Therapy for bacteremia caused by Staphylococcus aureus is often ineffective, even when treatment conditions are optimal according to experimental protocols. Adapted subclones, such as those bearing mutations that attenuate agr-mediated virulence activation, are associated with persistent infection and patient mortality. Therapy for bacteremia caused by Staphylococcus aureus is often ineffective, even when treatment conditions are optimal according to experimental protocols. Adapted subclones, such as those bearing mutations that attenuate agr-mediated virulence activation, are associated with persistent infection and patient mortality. To identify additional alterations in agr-defective mutants, we sequenced and assembled the complete genomes of clone pairs from colonizing and infected sites of several patients in whom S. aureus demonstrated a within-host loss of agr function. We report that events associated with agr inactivation result in agr-defective blood and nares strain pairs that are enriched in mutations compared to pairs from wild-type controls. The random distribution of mutations between colonizing and infecting strains from the same patient, and between strains from different patients, suggests that much of the genetic complexity of agr-defective strains results from prolonged infection or therapy-induced stress. However, in one of the agr-defective infecting strains, multiple genetic changes resulted in increased virulence in a murine model of bloodstream infection, bypassing the mutation of agr and raising the possibility that some changes were selected. Expression profiling correlated the elevated virulence of this agr-defective mutant to restored expression of the agr-regulated ESAT6-like type VII secretion system, a known virulence factor. Thus, additional mutations outside the agr locus can contribute to diversification and adaptation during infection by S. aureus agr mutants associated with poor patient outcomes.