The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-19¹. Coronaviruses have developed a variety of mechanisms to repress host mRNA translation to allow the translation of viral mRNA, and concomitantly block the cellular innate immune response^2,3. Although several different proteins of SARS-CoV-2 have previously been implicated in shutting off host expression^4,5,6,7, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here we combine RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA to comprehensively define the mechanisms that are used by SARS-CoV-2 to shut off cellular protein synthesis. We show that infection leads to a global reduction in translation, but that viral transcripts are not preferentially translated. Instead, we find that infection leads to the accelerated degradation of cytosolic cellular mRNAs, which facilitates viral takeover of the mRNA pool in infected cells. We reveal that the translation of transcripts that are induced in response to infection (including innate immune genes) is impaired. We demonstrate this impairment is probably mediated by inhibition of nuclear mRNA export, which prevents newly transcribed cellular mRNA from accessing ribosomes. Overall, our results uncover a multipronged strategy that is used by SARS-CoV-2 to take over the translation machinery and to suppress host defences.

冠状病毒 SARS-CoV-2 是导致 COVID-19 持续大流行的原因¹。冠状病毒已经发展出多种机制来抑制宿主 mRNA 的翻译，以允许病毒 mRNA 的翻译，并同时阻断细胞先天免疫反应^2,3。尽管 SARS-CoV-2 的几种不同蛋白质先前已涉及关闭宿主表达^4,5,6,7，缺乏关于 SARS-CoV-2 感染对细胞基因表达影响的全面了解。在这里，我们将 RNA 测序、核糖体分析和新合成 RNA 的代谢标记结合起来，全面定义 SARS-CoV-2 用来关闭细胞蛋白质合成的机制。我们表明感染导致全球翻译减少，但病毒转录本不优先翻译。相反，我们发现感染导致细胞溶质细胞 mRNA 的加速降解，这有助于病毒接管受感染细胞中的 mRNA 池。我们揭示了响应感染（包括先天免疫基因）诱导的转录物的翻译受损。我们证明这种损伤可能是由核 mRNA 输出的抑制介导的，阻止新转录的细胞 mRNA 进入核糖体。总体而言，我们的结果揭示了一种多管齐下的策略，SARS-CoV-2 使用该策略来接管翻译机器并抑制宿主防御。