SARS-CoV-2 is sensitive to type I interferon pretreatment

Kumari G. Lokugamage; Adam Hage; Craig Schindewolf; Ricardo Rajsbaum; Vineet D. Menachery

For SARS-CoV-2, the sensitivity to IFN-I indicates a distinction from SARS-CoV and 218 suggests differential host innate immune modulation between the viruses. The loss of ORF3b 219 and truncation/changes in ORF6 could signal a reduced capacity of SARS-CoV-2 to interfere 220 with type I IFN responses. For SARS-CoV ORF6, the N-terminal domain has been shown to 221 have a clear role in its ability to disrupt karyopherin transport (32); in turn, the loss of ORF6 222 function for SARS-CoV-2 would likely render it much more susceptible to IFN-I pretreatment as 223 activated STAT1 has the capacity to enter the nucleus and induce ISGs and the antiviral 224 response. In these studies, we have found that following IFN-I pretreatment, STAT1 225 phosphorylation is induced following SARS-CoV-2 infection. The increase in ISG proteins 226 . CC-BY-NC 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.07.982264 doi: bioRxiv preprint (STAT1, IFIT2, TRIM25) suggests that SARS-CoV-2 ORF6 does not effectively block nuclear 227 transport as well as SARS ORF6. For SARS-CoV ORF3b, the viral protein has been shown to 228 disrupt phosphorylation of IRF3, a key transcriptional factor in the induction of IFN-I and the 229 antiviral state (31). While its mechanism of action is not clear, the ORF3b absence in SARS-230