Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon
Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon
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DOI：
10.1038/ncomms4344
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发表时间：
2014-02-01
影响因子：
16.6
通讯作者：
Yu, Sung-Liang
中科院分区：
文献类型：
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作者：
Ho, Bing-Ching;Yu, I-Shing;Yu, Sung-Liang
目前还没有治疗肠病毒71型感染的抗病毒药物或疫苗。虽然病毒感染后引起的I型干扰素应答对于建立宿主抗病毒先天免疫至关重要，但EV71不能有效地诱导这种应答。在这里，我们通过证明ev71诱导的miR-146a中和通过重新启动I型干扰素的产生来防止小鼠死亡，为潜在的抗ev71治疗提供了新的见解。EV71感染上调miR-146a，其靶向IRAK1和TRAF6参与TLR信号传导和I型干扰素的产生。我们进一步确定AP1与ev71诱导的miR-146a表达有关。令人惊讶的是，在小鼠模型中，敲除miR-146a或通过特异性antagomiR中和病毒诱导的miR-146a可恢复IRAK1和TRAF6的表达，增加IFN β的产生，抑制病毒传播并提高存活率。我们的研究结果表明，肠病毒诱导的miR-146a通过抑制IFN的产生促进了病毒的发病机制，并为制定肠道病毒感染的预防和治疗策略提供了线索。
There are no antivirals or vaccines available to treat Enterovirus 71 (EV71) infections. Although the type I interferon response, elicited upon virus infection, is critical to establishing host antiviral innate immunity, EV71 fails to induce this response efficiently. Here we provide new insights into potential anti-EV71 therapy by showing that neutralization of EV71-induced miR-146a prevents death in mice by restarting the production of type I interferon. EV71 infection upregulates miR-146a, which targets IRAK1 and TRAF6 involved in TLR signalling and type I interferon production. We further identify AP1 as being responsible for the EV71-induced expression of miR-146a. Surprisingly, knocking out miR-146a or neutralizing virus-induced miR-146a by specific antagomiR restores expressions of IRAK1 and TRAF6, augments IFN beta production, inhibits viral propagation and improves survival in the mouse model. Our results suggest that enterovirus-induced miR-146a facilitates viral pathogenesis by suppressing IFN production and provide a clue to developing preventive and therapeutic strategies for enterovirus infections.