The RpoE Stress Response Pathway Mediates Reduction of the Virulence of Enteropathogenic Escherichia coli by Zinc.
The RpoE Stress Response Pathway Mediates Reduction of the Virulence of Enteropathogenic Escherichia coli by Zinc.
复制标题
RpoE 应激反应途径介导锌降低肠道病原性大肠杆菌的毒力。
DOI：
10.1128/aem.00507-15
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发表时间：
2015
影响因子：
4.4
通讯作者：
Mellies,JayL
中科院分区：
文献类型：
--
作者：
Xue,Yuan;Osborn,Jossef;Panchal,Anand;Mellies,JayL
补锌是治疗肠道病原菌引起的婴幼儿腹泻病的有效方法。以前的研究表明，锌直接作用于肠道致病大肠杆菌(EPEC)，在一定浓度下抑制几个毒力相关基因，这一浓度可以通过口服锌补充剂实现。Ourin体外研究表明，微摩尔浓度的锌诱导了EPEC的包膜应激反应并抑制了毒力，为锌的治疗作用提供了可能的机制解释。本文研究了锌对外周血管内皮细胞分子和生理的影响。我们发现微摩尔浓度的锌降低了细菌的生长速度，而不影响细菌的生存能力。我们观察到锌引起的细胞膜通透性增加。锌上调依赖于RpoE的包膜应激反应通路，抑制EPEC毒力基因的表达。RpoE本身就足以抑制毒力因子的表达，并减少对人类宿主细胞的附着和消除损伤的形成。通过突变分析，我们证明RpoE的DNA结合基序是抑制LEE1操纵子所必需的，而不是抑制LEE4操纵子所必需的。可以预见，抑制RpoE介导的包膜应激反应与微摩尔浓度的锌一起降低了EPEC的活力。综上所述，锌诱导EPEC的RpoE和应激反应通路，交替Sigma因子RpoE通过多种机制下调EPEC Lee和Non-Lee毒力基因。
Zinc supplements are an effective clinical treatment for infantile diarrheal disease caused by enteric pathogens. Previous studies demonstrated that zinc acts on enteropathogenic Escherichia coli (EPEC) bacteria directly to suppress several virulence-related genes at a concentration that can be achieved by oral delivery of dietary zinc supplements. Ourin vitrostudies showed that a micromolar concentration of zinc induced the envelope stress response and suppressed virulence in EPEC, providing a possible mechanistic explanation for zinc's therapeutic action. In this report, we investigated the molecular and physiological changes in EPEC induced by zinc. We found that micromolar concentrations of zinc reduced the bacterial growth rate without affecting viability. We observed increased membrane permeability caused by zinc. Zinc upregulated the RpoE-dependent envelope stress response pathway and suppressed EPEC virulence gene expression. RpoE alone was sufficient to inhibit virulence factor expression and to attenuate attaching and effacing lesion formation on human host cells. By mutational analysis we demonstrate that the DNA-binding motif of RpoE is necessary for suppression of theLEE1, but not theLEE4, operon. Predictably, inhibition of the RpoE-mediated envelope stress response in combination with micromolar concentrations of zinc reduced EPEC viability. In conclusion, zinc induces the RpoE and stress response pathways in EPEC, and the alternate sigma factor RpoE downregulates EPEC LEE and non-LEE virulence genes by multiple mechanisms.