CodY Deletion Enhances In Vivo Virulence of Community-Associated Methicillin-Resistant Staphylococcus aureus Clone USA300
CodY Deletion Enhances In Vivo Virulence of Community-Associated Methicillin-Resistant Staphylococcus aureus Clone USA300
复制标题
DOI：
10.1128/iai.06172-11
复制
发表时间：
2012-07-01
影响因子：
3.1
通讯作者：
Daum, Robert S.
中科院分区：
文献类型：
--
作者：
Montgomery, Christopher P.;Boyle-Vavra, Susan;Daum, Robert S.
金黄色葡萄球菌全局调节因子CodY通过控制靶基因的表达来响应营养可利用性。在体外，CodY抑制毒力基因的转录，但尚不清楚CodY在体内是否也抑制毒力。主要的社区相关耐甲氧西林金黄色葡萄球菌（CA-MRSA）克隆USA300是高毒力的，并且增加了全球调节因子和毒力基因的转录；这些特征使人想起CodY中的一种缺陷菌株。然而，序列分析显示，USA300和其他序列金黄色葡萄球菌分离株的codY基因与已知具有活性codY的菌株的codY基因没有显著差异。codY在USA300以及其他被评估的脉搏型中表达。从USA300临床分离物中删除codY导致全球调节因子agr和saeRS以及编码毒素α -溶血素（hla）的基因的表达适度增加。在codY突变体中，lukF-PV基因（编码Panton-Valentine leukocidin （PVL）的一部分）的表达显著增加（约30倍）。通过与功能性codY基因的互补，所有这些表达差异都被逆转。此外，纯化的CodY蛋白结合在lukSF-PV操纵子的上游，表明CodY直接抑制lukSF-PV的表达。codY的缺失增加了USA300在坏死性肺炎和皮肤感染中的毒力。有趣的是，从codY突变体中删除lukSF-PV并没有减弱毒力，这表明codY突变体的高毒力并不是由PVL的过表达来解释的。这些结果表明，CodY在USA300中具有活性，并且CodY介导的抑制抑制了USA300的毒力。
The Staphylococcus aureus global regulator CodY responds to nutrient availability by controlling the expression of target genes. In vitro, CodY represses the transcription of virulence genes, but it is not known if CodY also represses virulence in vivo. The dominant community-associated methicillin-resistant S. aureus (CA-MRSA) clone, USA300, is hypervirulent and has increased transcription of global regulators and virulence genes; these features are reminiscent of a strain defective in CodY. Sequence analysis revealed, however, that the codY genes of USA300 and other sequenced S. aureus isolates are not significantly different from the codY genes in strains known to have active CodY. codY was expressed in USA300, as well as in other pulsotypes assessed. Deletion of codY from a USA300 clinical isolate resulted in modestly increased expression of the global regulators agr and saeRS, as well as the gene encoding the toxin alpha-hemolysin (hla). A substantial increase (>30-fold) in expression of the lukF-PV gene, encoding part of the Panton-Valentine leukocidin (PVL), was observed in the codY mutant. All of these expression differences were reversed by complementation with a functional codY gene. Moreover, purified CodY protein bound upstream of the lukSF-PV operon, indicating that CodY directly represses expression of lukSF-PV. Deletion of codY increased the virulence of USA300 in necrotizing pneumonia and skin infection. Interestingly, deletion of lukSF-PV from the codY mutant did not attenuate virulence, indicating that the hypervirulence of the codY mutant was not explained by overexpression of PVL. These results demonstrate that CodY is active in USA300 and that CodY-mediated repression restrains the virulence of USA300.