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首页> 外文期刊>Infection and immunity >Protection against Shiga-Toxigenic Escherichia coli by Non-Genetically Modified Organism Receptor Mimic Bacterial Ghosts
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Protection against Shiga-Toxigenic Escherichia coli by Non-Genetically Modified Organism Receptor Mimic Bacterial Ghosts

机译：非转基因修饰的生物受体模拟细菌对志贺毒素大肠杆菌的保护作用。

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Shiga-toxigenic Escherichia coli (STEC) causes severe gastrointestinal infections in humans that may lead to life-threatening systemic sequelae, such as the hemolytic uremic syndrome (HUS). Rapid diagnosis of STEC infection early in the course of disease opens a window of opportunity for therapeutic intervention, for example, by administration of agents that neutralize Shiga toxin (Stx) in the gut lumen. We previously developed a recombinant bacterium that expresses a mimic of the Stx receptor globotriaosyl ceramide (Gb3) on its surface through modification of the lipopolysaccharide (A. W. Paton, R. Morona, and J. C. Paton, Nat Med 6:265–270, 2000, http://dx.doi.org/10.1038/73111). This construct was highly efficacious in vivo, protecting mice from otherwise fatal STEC disease, but the fact that it is a genetically modified organism (GMO) has been a barrier to clinical development. In the present study, we have overcome this issue by development of Gb3 receptor mimic bacterial ghosts (BGs) that are not classified as GMOs. Gb3-BGs neutralized Stx1 and Stx2 in vitro with high efficiency, whereas alternative Gb3-expressing non-GMO subbacterial particles (minicells and outer membrane blebs) were ineffective. Gb3-BGs were highly efficacious in a murine model of STEC disease. All mice (10/10) treated with Gb3-BGs survived challenge with a highly virulent O113:H21 STEC strain and showed no pathological signs of renal injury. In contrast, 6/10 mice treated with control BGs succumbed to STEC challenge, and survivors exhibited significant weight loss, neutrophilia, and histopathological evidence of renal damage. Thus, Gb3-BGs offer a non-GMO approach to treatment of STEC infection in humans, particularly in an outbreak setting.
机译：产志贺毒素的大肠杆菌（STEC）在人中引起严重的胃肠道感染，可能导致危及生命的全身后遗症，例如溶血性尿毒症综合征（HUS）。在疾病过程早期对STEC感染的快速诊断打开了治疗干预的机会之窗，例如，通过在肠腔内施用中和志贺毒素（Stx）的药物。我们以前开发了一种重组细菌，该细菌通过修饰脂多糖在其表面上表达Stx受体球果糖基神经酰胺（Gb3）的模拟物（AW Paton，R. Morona和JC Paton，Nat Med 6：265-270，2000，http ：//dx.doi.org/10.1038/73111）。这种构建体在体内非常有效，可以保护小鼠免受致命的STEC疾病的侵害，但是它是转基因生物（GMO）的事实已成为临床发展的障碍。在本研究中，我们通过开发未归类为GMO的Gb3受体模拟细菌幽灵（BG）克服了这个问题。 Gb3-BGs在体外高效中和了Stx1和Stx2，而其他表达Gb3的非GMO亚细菌颗粒（小细胞和外膜泡）无效。 Gb3-BGs在STEC疾病的鼠模型中非常有效。用Gb3-BGs处理的所有小鼠（10/10）在高毒性的O113：H21 STEC菌株中均能存活，且未显示肾脏损伤的病理迹象。相反，用对照BG治疗的6/10小鼠死于STEC攻击，幸存者表现出明显的体重减轻，中性粒细胞减少和肾脏损害的组织病理学证据。因此，Gb3-BG提供了一种非转基因的方法来治疗人类的STEC感染，特别是在暴发环境中。

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