Abstract
Two highly pathogenic human coronaviruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) have evolved proteins that can inhibit host antiviral responses, likely contributing to disease progression and high case-fatality rates. SARS-CoV-2 emerged in December 2019 resulting in a global pandemic. Recent studies have shown that SARS-CoV-2 is unable to induce a robust type I interferon (IFN) response in human cells, leading to speculation about the ability of SARS-CoV-2 to inhibit innate antiviral responses. However, innate antiviral responses are dynamic in nature and gene expression levels rapidly change within minutes to hours. In this study, we have performed a time series RNA-seq and selective immunoblot analysis of SARS-CoV-2 infected lung (Calu-3) cells to characterize early virus-host processes. SARS-CoV-2 infection upregulated transcripts for type I IFNs and interferon stimulated genes (ISGs) after 12 hours. Furthermore, we analyzed the ability of SARS-CoV-2 to inhibit type I IFN production and downstream antiviral signaling in human cells. Using exogenous stimuli, we discovered that SARS-CoV-2 is unable to modulate IFNβ production and downstream expression of ISGs, such as IRF7 and IFIT1. Thus, data from our study indicate that SARS-CoV-2 may have evolved additional mechanisms, such as masking of viral nucleic acid sensing by host cells to mount a dampened innate antiviral response. Further studies are required to fully identify the range of immune-modulatory strategies of SARS-CoV-2.
Significance Highly pathogenic coronaviruses that cause SARS and MERS have evolved proteins to shutdown antiviral responses. The emergence and rapid spread of SARS-CoV-2, along with its relatively low case-fatality rate have led to speculation about its ability to modulate antiviral responses. We show that SARS-CoV-2 is unable to block antiviral responses that are mounted by exogenous stimuli. Data from our study provide promising support for the use of recombinant type I IFN as combination therapy to treat COVID-19 patients. Furthermore, our data also suggest that the inability of SARS-CoV-2 to efficiently modulate antiviral responses may be associated with its low case-fatality rate compared to other pathogenic CoVs that cause SARS and MERS.
Competing Interest Statement
This study was supported by a Canadian Institutes of Health Research (CIHR) COVID-19 rapid response grant to principal applicant K.M. and Co-Applicants A.B., A.G.M., M.S.M. and S.M. A.B. was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC). Computer resources were in part supplied by the McMaster Service Lab and Repository computing cluster, funded in part by grants to A.G.M. from the Canadian Foundation for Innovation. J.A.H. is supported by the Canada Research Chairs Program and an Ontario Early Career Researcher Award. M.S.M. is supported by a CIHR COVID-19 rapid response grant, a CIHR New Investigator Award and an Ontario Early Researcher Award.
