Stanley Ho Center for Emerging Infectious Diseases and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong,China.
J Virol. 2012 Apr;86(7):3767-76. doi: 10.1128/JVI.06687-11. Epub 2012 Jan 18.
The recent outbreak of enterovirus 71 (EV71) infected millions of children and caused over 1,000 deaths. To date, neither an effective vaccine nor antiviral treatment is available for EV71 infection. Interferons (IFNs) have been successfully applied to treat patients with hepatitis B and C viral infections for decades but have failed to treat EV71 infections. Here, we provide the evidence that EV71 antagonizes type I IFN signaling by reducing the level of interferon receptor 1 (IFNAR1). We show that the host cells could sense EV71 infection and stimulate IFN-β production. However, the induction of downstream IFN-stimulated genes is inhibited by EV71. Also, only a slight interferon response and antiviral effects could be detected in cells treated with recombinant type I IFNs after EV71 infection. Further studies reveal that EV71 blocks the IFN-mediated phosphorylation of STAT1, STAT2, Jak1, and Tyk2 by reducing IFNAR1. Finally, we identified the 2A protease encoded by EV71 as an antagonist of IFNs and show that the protease activity is required for reducing IFNAR1 levels. Taken together, our study for the first time uncovers a mechanism used by EV71 to antagonize type I IFN signaling and provides new targets for future antiviral strategies.
肠道病毒 71 型（EV71）近期爆发感染了数百万儿童，并导致超过 1000 人死亡。迄今为止，尚无针对 EV71 感染的有效疫苗或抗病毒治疗方法。干扰素（IFNs）已成功应用于治疗乙型和丙型肝炎病毒感染患者数十年，但未能治疗 EV71 感染。在这里，我们提供了 EV71 通过降低干扰素受体 1（IFNAR1）水平来拮抗 I 型干扰素信号的证据。我们表明宿主细胞可以感知 EV71 感染并刺激 IFN-β 的产生。然而，EV71 抑制了下游 IFN 刺激基因的诱导。此外，在 EV71 感染后用重组 I 型 IFNs 处理的细胞中，仅检测到轻微的干扰素反应和抗病毒作用。进一步的研究表明，EV71 通过减少 IFNAR1 来阻断 IFN 介导的 STAT1、STAT2、Jak1 和 Tyk2 的磷酸化。最后，我们确定了 EV71 编码的 2A 蛋白酶是 IFN 的拮抗剂，并表明蛋白酶活性对于降低 IFNAR1 水平是必需的。总之，我们的研究首次揭示了 EV71 拮抗 I 型 IFN 信号的机制，并为未来的抗病毒策略提供了新的靶标。
