Characterizing the Dynamics of the Type I Interferon Response in SARS-CoV-2 Infection to Identify ISGs that Serve as Possible Antiviral Restriction Factors

Abstract

Previous work has implicated a dysregulated IFN signaling pathway in severe cases of COVID-19 and found that treatment of IFNs in severe patients can decrease viral load. Here, we characterize the response to type I interferon to reveal the ISG signature of Calu-3 and ACE2/HSAEC1-KT cells after IFN-β treatment to identify specific ISGs as putative antiviral effector genes that may impart antiviral properties to inhibit SARS-CoV-2 replication. Treatment of IFN-β prior to SARS-CoV-2 infection regulated the expression of hundreds of ISGs resulting in early clearance of SARS-CoV-2 viral RNA. On the other hand, treatment of IFN-β after SARS-CoV-2 infection results in only minor changes in gene expression, owing to virus-directed blockades to the interferon signaling pathway and is not correlated with a decrease in SARS-CoV-2 RNA. Thus, early induction of the IFN signaling pathway indicates the ability for ISGs to quickly control SARS-CoV-2 infection whereas establishing the viral blockade to interferon signaling allows the virus to escape interferon actions later in the infection cycle. These studies show that after 24 hours of SARS-CoV-2 infection, the IFN signaling pathway is not able to overcome virus-controlled gene regulation, setting the stage for infection progression and disease. Thus, early ISG expression is essential for the control of SARS-CoV-2 infection.