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.
【저자키워드】 SARS-CoV-2, Innate immunity, interferon, IRF3, mRNA export, RNase L, mRNA decay, 【초록키워드】 immune response, Antiviral, SARS-COV-2 infection, Transcription, RNA, Regulatory, Protein, serum, viral replication, mRNA, Patient, IFN, Degradation, dissemination, expression, early stage, SARS-CoV-2 replication, severe COVID-19 disease, Signaling, antiviral response, RNase, mRNAs, Trigger, Type III IFN, transcription factor, cytoplasm, Transport, type I, hallmark, nucleus, SARS-CoV-2 infected cells, second, biogenesis, translocation, mammalian, Host, Genes, widespread, limit, transcriptional, host mRNA, performed, caused, inhibit, inhibited, elevated, cytoplasmic, the interferon, the SARS-CoV-2, 【제목키워드】 SARS-COV-2 infection, Trigger, widespread, host mRNA,