The PerR regulon in peroxide resistance and virulence of Streptococcus pyogenes
The PerR regulon in peroxide resistance and virulence of Streptococcus pyogenes
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DOI：
10.1111/j.1365-2958.2004.04370.x
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发表时间：
2005-01-01
影响因子：
3.6
通讯作者：
Caparon, MG
中科院分区：
文献类型：
--
作者：
Brenot, A;King, KY;Caparon, MG
先前的研究表明，过氧化氢酶缺乏的病原菌化脓性链球菌(A组)具有很强的抵抗氧化应激的能力，这部分涉及转录调控因子PerR。然而，Perr调节子的范围和该调节子成员对毒力的贡献尚不清楚。在这项研究中，DNase I足迹显示，PerR特异性地结合到编码烷基过氧化氢还原酶(AhpC)基因启动子上游的单个位置。然而，对转录丰度的分析表明，虽然ahpC受生长阶段的调控，但其调控不受PerR的影响。相反，PERR调节一个分化基因簇的转录，该基因簇编码一种假定的冷休克蛋白。编码类DPS过氧化氢抗性蛋白MRGA的基因被PERR抑制，这与其启动子中存在PERR结合位点的情况一致。Perr(-)、AhpC(-)和mrga(-)突变体的表型分析表明，虽然AhpC在体外对过氧化氢的抵抗不是必需的，但AhpC确实有助于清除内源性过氧化氢，并在小鼠感染模型中是毒力所必需的。相比之下，mrga(-)突变体在体外对过氧化氢的挑战高度敏感，但在所有测试的动物模型中都是完全毒力的。最后，PerR(-)突变体对过氧化氢高度抵抗，但在所有小鼠模型中毒力都高度减弱。这些数据表明，虽然突变株抵抗过氧化应激的能力与其致病能力并不直接相关，但对过氧化应激反应的适当调控对毒力至关重要。
Prior studies have shown that the catalase-deficient pathogen Streptococcus pyogenes (group A streptococcus) has a robust ability to resist oxidative stress that partially involves the transcriptional regulator PerR. However, the extent of the PerR regulon and the contribution of the members of this regulon to virulence are unknown. In this study, DNase I footprinting revealed that PerR binds specifically to a single site upstream of the promoter for the gene encoding alkyl hydroperoxide reductase (ahpC). However, analyses of transcript abundance revealed that while ahpC is regulated in response to growth phase, its regulation is independent of PerR. Instead, PerR regulates transcription of a divergent gene cluster that encodes a putative cold shock protein. The gene encoding the Dps-like peroxide resistance protein MrgA was repressed by PerR, consistent with the presence of a PerR binding site in its promoter. Phenotypic analyses of PerR(-), AhpC(-) and MrgA(-) mutants revealed that while AhpC is not essential for resistance to challenge with hydrogen peroxide in vitro, AhpC does contribute to scavenging of endogenous hydrogen peroxide and is required for virulence in a murine model of infection. In contrast, a MrgA(-) mutant was hypersensitive to challenge with peroxide in vitro, but was fully virulent in all animal models tested. Finally, a PerR(-) mutant was hyper-resistant to peroxide, yet was highly attenuated for virulence in all murine models. These data demonstrate that while a mutant's capacity to resist peroxide stress did not directly correlate with its ability to cause disease, the appropriate regulation of the peroxide stress response is critical for virulence.