TrxR, a new CovR-repressed response regulator that activates the Mga virulence regulon in group A streptococcus
TrxR, a new CovR-repressed response regulator that activates the Mga virulence regulon in group A streptococcus
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DOI：
10.1128/iai.00597-08
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发表时间：
2008-10-01
影响因子：
3.1
通讯作者：
McIver, Kevin S.
中科院分区：
文献类型：
--
作者：
Leday, Temekka V.;Gold, Kathryn M.;McIver, Kevin S.
A组链球菌（GAS）化脓性链球菌对毒力因子的协调调节在该病原体引起疾病的能力中是重要的。为了进一步阐明这种人类病原体中的调控网络，基于其与肺炎链球菌中毒力相关TCS的同源性，选择CovR抑制的双组分系统（TCS）trxSR进行进一步分析。在小鼠皮肤感染模型中，反应调节基因trxR的插入突变导致病变大小、病变严重程度和致死率显著降低。治愈trxR突变恢复了与野生型菌株相当的毒力。trxSR操纵子在体内被定义，并且发现CovR在体外直接抑制其启动子。DNA微阵列分析表明，TrxR激活Mga调控的毒力基因的转录，这可能解释了trxR突变体的毒力衰减。这种调节似乎是通过激活mga启动子Pmga而发生的，如荧光素酶报告融合物的分析所证明的。用质粒上的trxR互补trxR突变体恢复了Mga调节子基因的表达，并将小鼠模型中的毒力恢复到野生型水平。TrxR是第一个显示调节Mga表达的TCS。因为它是CovR抑制，TrxR定义了一个新的途径，CovR可以影响Mga影响GAS的发病机制。
Coordinate regulation of virulence factors by the group A streptococcus (GAS) Streptococcus pyogenes is important in this pathogen's ability to cause disease. To further elucidate the regulatory network in this human pathogen, the CovR-repressed two-component system (TCS) trxSR was chosen for further analysis based on its homology to a virulence-related TCS in Streptococcus pneumoniae. In a murine skin infection model, an insertion mutation in the response regulator gene, trxR, led to a significant reduction in lesion size, lesion severity, and lethality. Curing the trxR mutation restored virulence comparable to the wild-type strain. The trxSR operon was defined in vivo, and CovR was found to directly repress its promoter in vitro. DNA microarray analysis established that TrxR activates transcription of Mga-regulated virulence genes, which may explain the virulence attenuation of the trxR mutant. This regulation appears to occur by activation of the mga promoter, Pmga, as demonstrated by analysis of a luciferase reporter fusion. Complementation of the trxR mutant with trxR on a plasmid restored expression of Mga regulon genes and restored virulence in the mouse model to wild-type levels. TrxR is the first TCS shown to regulate Mga expression. Because it is CovR repressed, TrxR defines a new pathway by which CovR can influence Mga to affect pathogenesis in the GAS.