Inhibition of Antiviral Innate Immunity by Birnavirus VP3 Protein via Blockage of Viral Double-Stranded RNA Binding to the Host Cytoplasmic RNA Detector MDA5
Inhibition of Antiviral Innate Immunity by Birnavirus VP3 Protein via Blockage of Viral Double-Stranded RNA Binding to the Host Cytoplasmic RNA Detector MDA5
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DOI：
10.1128/jvi.01115-14
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发表时间：
2014-10-01
影响因子：
5.4
通讯作者：
Zhou, Jiyong
中科院分区：
文献类型：
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作者：
Ye, Chengjin;Jia, Lu;Zhou, Jiyong
鸡MDA 5（chMDA 5）是鸡细胞质病毒RNA的唯一已知模式识别受体，启动I型干扰素（IFN）的产生。传染性法氏囊病病毒（IBDV）逃避宿主天然免疫，但其机制尚不清楚。我们在此报道IBDV通过chMDA 5依赖性信号通路抑制抗病毒天然免疫。IBDV感染并不诱导有效的I型干扰素（IFN）的产生，但拮抗β干扰素（IFN-β）在用IFN-α/β预处理的DF-1细胞中的抗病毒活性。双荧光素酶测定和诱导表达系统证明，IBDV蛋白VP 3显著抑制由裸IBDV基因组双链RNA（dsRNA）刺激的IFN-β表达。在体外和体内，VP 3蛋白与chMDA 5强烈竞争结合IBDV基因组dsRNA，并且来自其它双RNA病毒的VP 3也结合dsRNA。定点诱变证实VP 3 dsRNA结合结构域的缺失恢复了IFN-β表达。结果表明，VP 3通过阻断病毒基因组dsRNA与MDA 5的结合而抑制抗病毒天然免疫。IMPORTANCEMDA 5是一种已知的模式识别受体和细胞质病毒RNA传感器，在宿主抗病毒天然免疫中起着关键作用。许多病原体逃避或抑制宿主的抗病毒免疫应答，但大多数病原体所涉及的机制尚不清楚。我们在这里报告，双RNA病毒通过MDA 5依赖的信号通路抑制宿主的抗病毒先天免疫。在双RNA病毒感染期间，涉及IFN-β的抗病毒先天免疫系统没有有效地发挥作用，并且病毒蛋白VP 3显著抑制由裸病毒基因组dsRNA刺激的IFN-β表达。我们还表明，VP 3阻断MDA 5结合病毒基因组dsRNA在体外和体内。我们的数据表明，双RNA病毒编码的病毒蛋白VP 3是抗病毒先天免疫应答的抑制剂，并通过MDA 5依赖的信号通路抑制抗病毒先天免疫应答。
Chicken MDA5 (chMDA5), the sole known pattern recognition receptor for cytoplasmic viral RNA in chickens, initiates type I interferon (IFN) production. Infectious bursal disease virus (IBDV) evades host innate immunity, but the mechanism is unclear. We report here that IBDV inhibited antiviral innate immunity via the chMDA5-dependent signaling pathway. IBDV infection did not induce efficient type I interferon (IFN) production but antagonized the antiviral activity of beta interferon (IFN-beta) in DF-1 cells pretreated with IFN-alpha/beta. Dual-luciferase assays and inducible expression systems demonstrated that IBDV protein VP3 significantly inhibited IFN-beta expression stimulated by naked IBDV genomic double-stranded RNA (dsRNA). The VP3 protein competed strongly with chMDA5 to bind IBDV genomic dsRNA in vitro and in vivo, and VP3 from other birnaviruses also bound dsRNA. Site-directed mutagenesis confirmed that deletion of the VP3 dsRNA binding domain restored IFN-beta expression. Our data demonstrate that VP3 inhibits antiviral innate immunity by blocking binding of viral genomic dsRNA to MDA5.IMPORTANCEMDA5, a known pattern recognition receptor and cytoplasmic viral RNA sensor, plays a critical role in host antiviral innate immunity. Many pathogens escape or inhibit the host antiviral immune response, but the mechanisms involved are unclear for most pathogens. We report here that birnaviruses inhibit host antiviral innate immunity via the MDA5-dependent signaling pathway. The antiviral innate immune system involving IFN-beta did not function effectively during birnavirus infection, and the viral protein VP3 significantly inhibited IFN-beta expression stimulated by naked viral genomic dsRNA. We also show that VP3 blocks MDA5 binding to viral genomic dsRNA in vitro and in vivo. Our data reveal that birnavirus-encoded viral protein VP3 is an inhibitor of the antiviral innate immune response and inhibits the antiviral innate immune response via the MDA5-dependent signaling pathway.