Rapid Decay of Host Basal mRNAs During SARS-CoV-2 Infection Perturbs Host Antiviral mRNA Biogenesis and Export

Abstract

A key feature of the mammalian antiviral response is the transcriptional induction of interferon (IFN) genes, which encode for secreted proteins that prime the antiviral response to limit viral replication and dissemination. A hallmark of severe COVID-19 disease caused by SARS-CoV-2 is the low presence of IFNs in patient serum despite elevated levels of IFN-encoding mRNAs, indicative of post-transcriptional inhibition of IFN protein production. Herein, we show SARS-CoV-2 infection limits type I and type III IFN biogenesis by preventing the release of mRNA from their sites of transcription and/or triggering their nuclear degradation. Additionally, SARS-CoV-2 infection inhibits nuclear-cytoplasmic transport of IFN mRNAs as a consequence of widespread cytosolic mRNA degradation mediated by both the host antiviral endoribonuclease, RNase L, and by the SARS-CoV-2 protein, Nsp1. Thus, inhibition of host and/or viral Nsp1-mediated mRNA decay, as well as IFN treatments, may reduce viral-associated pathogenesis by promoting the innate immune response.Funding Information: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number F32AI145112 (J.M.B), funds from HHMI (Roy Parker), and support provided by the Office of the Vice President for Research and the Dept. of Microbiology, Immunology and Pathology at Colorado State University (Rushika Perera).Declaration of Interests: Roy Parker is a founder and consultant of Faze Medicines.