Type I Interferon Susceptibility Distinguishes SARS-CoV-2 from SARS-CoV

Abstract

SARS-CoV-2, a novel coronavirus (CoV) that causes COVID-19, has recently emerged causing an ongoing outbreak of viral pneumonia around the world. While distinct from SARS-CoV, both group 2B CoVs share similar genome organization, origins to bat CoVs, and an arsenal of immune antagonists. In this report, we evaluate type-I interferon (IFN-I) sensitivity of SARS-CoV-2 relative to the original SARS-CoV. Our results indicate that while SARS-CoV-2 maintains similar viral replication to SARS-CoV, the novel CoV is much more sensitive to IFN-I. In Vero E6 and in Calu3 cells, SARS-CoV-2 is substantially attenuated in the context of IFN-I pretreatment, while SARS-CoV is not. In line with these findings, SARS-CoV-2 fails to counteract phosphorylation of STAT1 and expression of ISG proteins, while SARS-CoV is able to suppress both. Comparing SARS-CoV-2 and influenza A virus in human airway epithelial cultures (HAEC), we observe the absence of IFN-I stimulation by SARS-CoV-2 alone, but detect failure to counteract STAT1 phosphorylation upon IFN-I pretreatment resulting in near ablation of SARS-CoV-2 infection. Next, we evaluated IFN-I treatment post infection and found SARS-CoV-2 was sensitive even after establishing infection. Finally, we examined homology between SARS-CoV and SARS-CoV-2 in viral proteins shown to be interferon antagonists. The absence of an equivalent open reading frame (ORF) 3b and genetic differences to ORF6 suggest the two key IFN-I antagonists may not maintain equivalent function in SARS-CoV-2. Together, the results identify key differences in susceptibility to IFN-I responses between SARS-CoV and SARS-CoV-2 that may help inform disease progression, treatment options, and animal model development. IMPORTANCE With the ongoing outbreak of COVID-19, differences between SARS-CoV-2 and the original SARS-CoV could be leveraged to inform disease progression and eventual treatment options. In addition, these findings could have key implications for animal model development as well as further research into how SARS-CoV-2 modulates the type I IFN response early during infection.

A novel cell culture system modeling the SARS-CoV-2 life cycle

“…6A). This is consistent with recent reports that SARS-CoV-2 is sensitive to type I interferon treatment 11,[25][26][27] .…”

Bovine Interferon Lambda Is a Potent Antiviral Against SARS-CoV-2 Infection in vitro

“…Lokugamage et al recently demonstrated that a pretreatment of VERO cells with 1,000 IU/ml of human IFN-α caused a 2-log 10 drop in viral titer at 48 dpi as compared to control untreated cells (47). We found the same result but using 0.14 IU/ml of rbIFN-λ.…”

“…Several studies show that type I and type III IFNs are effective in reducing SARS-CoV-2 replication in VERO cells (18,19,47).…”

Randomized controlled open label trial on the use of favipiravir combined with inhaled interferon beta-1b in hospitalized patients with moderate to severe COVID-19 pneumonia

“…Type I interferons (such as IFN-α, IFN-β) have been shown in clinical trials during the SARS epidemic to have the ability to inhibit the replication of SARS-CoV-1 and therefore improve clinical outcomes (Moriguchi and Sato, 2003). A recent study has shown that SARS-CoV-2 was sensitive to type I inhaled interferon pretreatment in vero cells (Lokugamage et al, 2020) and a small pilot non-randomized study on 33 patients with moderate COVID-19 pneumonia showed that the use of inhaled interferon IFN-k combined with trefoil factor 2 (TFF2), a secreted polypeptide resistant to degradation and hydrolysis, protects the gastrointestinal tract from microbial or chemical induced injury, and was associated with clinical and radiological improvement and viral reversion, therefore resulting in shorter length of stay (Fu et al, 2020). A randomized double-blind placebo-controlled trial to determine the safety and efficacy of inhaled IFN-β1a (SNG001for nebulisation) for patients infected with SARS-CoV-2 is ongoing (ClinicalTrials.gov Identifier: NCT04385095).…”