SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3.
SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3.
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DOI：
10.3389/fcimb.2021.789462
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发表时间：
2021
影响因子：
5.7
通讯作者：
Parvatiyar K
中科院分区：
文献类型：
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作者：
Freitas RS;Crum TF;Parvatiyar K
2019冠状病毒病（COVID-19）的发病机制与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）密切相关，疾病严重程度与I型干扰素（IFN-I）细胞因子的诱导受损有关，这些细胞因子协调对病毒感染的先天免疫反应。在这里，我们确定了SARS-CoV-2编码的蛋白质，刺突，作为一种干扰素-I的抑制剂，拮抗病毒RNA模式识别受体RIG-I信号。SARS-CoV-2 Spike的异位表达阻断了RIG-I介导的IFNβ激活和下游干扰素刺激基因的诱导。因此，与对照细胞相比，SARS-CoV-2刺突表达细胞具有增加的RNA病毒负荷。免疫共沉淀实验显示SARS-CoV-2刺突与干扰素调节因子3（IRF 3）相关，IRF 3是一种控制IFN-I激活的关键转录因子。通过免疫测定的共表达分析进一步表明，Spike特异性抑制IRF 3表达，因为NF-κB和STAT 1转录因子水平保持完整。进一步的生化实验发现，SARS-CoV-2刺突增强了IRF 3的蛋白酶体降解，这暗示了SARS-CoV-2逃避宿主先天抗病毒免疫应答以促进COVID-19发病的新机制。
Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis.