The transcriptional induction of interferon (IFN) genes is a key feature of the mammalian antiviral response that limits viral replication and dissemination. A hallmark of severe COVID-19 disease caused by SARS-CoV-2 is the low presence of IFN proteins in patient serum despite elevated levels of IFN-encoding mRNAs, indicative of post-transcriptional inhibition of IFN protein production. Here, we performed single-molecule RNA visualization to examine the expression and localization of host mRNAs during SARS-CoV-2 infection. Our data show that the biogenesis of type I and type III IFN mRNAs is inhibited at multiple steps during SARS-CoV-2 infection. First, translocation of the interferon regulatory factor 3 (IRF3) transcription factor to the nucleus is limited in response to SARS-CoV-2, indicating that SARS-CoV-2 inhibits RLR-MAVS signaling and thus weakens transcriptional induction of IFN genes. Second, we observed that IFN mRNAs primarily localize to the site of transcription in most SARS-CoV-2 infected cells, suggesting that SARS-CoV-2 either inhibits the release of IFN mRNAs from their sites of transcription and/or triggers decay of IFN mRNAs in the nucleus upon exiting the site of transcription. Lastly, nuclear-cytoplasmic transport of IFN mRNAs is inhibited during SARS-CoV-2 infection, which we propose is a consequence of widespread degradation of host cytoplasmic basal mRNAs in the early stages of SARS-CoV-2 replication by the SARS-CoV-2 Nsp1 protein, as well as the host antiviral endoribonuclease, RNase L. Importantly, IFN mRNAs can escape SARS-CoV-2-mediated degradation if they reach the cytoplasm, making rescue of mRNA export a viable means for promoting the immune response to SARS-CoV-2.

中文翻译：

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SARS-CoV-2 感染引发广泛的宿主 mRNA 衰减，导致 mRNA 输出阻断

干扰素( IFN ) 基因的转录诱导是限制病毒复制和传播的哺乳动物抗病毒反应的关键特征。由 SARS-CoV-2 引起的严重 COVID-19 疾病的一个标志是，尽管编码IFN 的mRNA水平升高，但患者血清中 IFN 蛋白的含量较低，这表明 IFN 蛋白产生的转录后抑制。在这里，我们进行了单分子 RNA 可视化，以检查 SARS-CoV-2 感染期间宿主 mRNA 的表达和定位。我们的数据表明 I 型和 III 型干扰素的生物发生在 SARS-CoV-2 感染期间，mRNA 在多个步骤中受到抑制。首先，干扰素调节因子 3 (IRF3) 转录因子向细胞核的易位在响应 SARS-CoV-2 时受到限制，表明 SARS-CoV-2 抑制了 RLR-MAVS 信号传导，从而削弱了IFN基因的转录诱导。其次，我们观察到IFN mRNA 主要定位于大多数 SARS-CoV-2 感染细胞的转录位点，这表明 SARS-CoV-2 要么抑制了IFN mRNA 从其转录位点的释放和/或触发了IFN 的衰变mRNA 在离开转录位点后进入细胞核。最后，干扰素的核质转运在 SARS-CoV-2 感染期间 mRNA 被抑制，我们认为这是 SARS-CoV-2 Nsp1 蛋白在 SARS-CoV-2 复制的早期阶段广泛降解宿主细胞质基础 mRNA 的结果，以及宿主抗病毒内切核糖核酸酶，RNase L。重要的是，如果IFN mRNA 到达细胞质，则它们可以逃避 SARS-CoV-2 介导的降解，这使得拯救 mRNA 输出成为促进对 SARS-CoV-2 免疫反应的可行手段。