Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV

Abstract

Article Summary: SARS-CoV-2 has similar replication kinetics to SARS-CoV, but demonstrates significant sensitivity to type I interferon treatment. Running title: SARS-CoV-2 sensitive to type I IFN pretreatmentAbstract 1 SARS-CoV-2, a novel coronavirus (CoV), has recently emerged causing an ongoing outbreak of 2 viral pneumonia around the world. While genetically distinct from the original SARS-CoV, both 3 group 2B coronaviruses share similar genome organization and origins to coronaviruses 4 harbored in bats. Importantly, initial guidance has used insights from SARS-CoV infection to 5 inform treatment and public health strategies. In this report, we evaluate SARS-CoV-2 relative to 6 the original SARS-CoV. Our results indicate that while SARS-CoV-2 maintains similar viral 7 replication kinetics to SARS-CoV in Vero cell, the novel coronavirus is much more sensitive to 8 type I interferon pretreatment. We subsequently examined homology between SARS-CoV and 9SARS-CoV-2 in viral proteins shown to be interferon antagonist. The absence of open reading 10 frame (ORF) 3b and significant changes to ORF6 suggest the two key IFN antagonists may not 11 maintain equivalent function in SARS-CoV-2. Together, the results identify key differences in 12 susceptibility to the IFN response between SARS-CoV and SARS-CoV-2 that could help inform 13 disease progression, treatment options, and animal model development.

Type 1 interferons as a potential treatment against COVID-19

“…Supporting this hypothesis, it was shown that IFNα2b sprays can reduce the infection rate of SARS-CoV-2 (Shen and Yang, 2020). This study shows that IFN-I can be used as a prophylaxis against SARS-CoV-2, which is confirmed by the in vitro efficacy of interferon pretreatment against the virus (Lokugamage et al, 2020), while the replication of MERS-CoV (Sheahan et al, 2020) and SARS-CoV (Menachery et al, 2014;Thiel and Weber, 2008), was reported to be indifferent to IFN-I prophylaxis.…”

“…Similarly, the Orf3b protein of SARS-CoV inhibits the phosphorylation of IRF3 , a protein involved in the activation of IFN expression. However, the Orf6 and Orf3b proteins of SARS-CoV-2 are truncated (Lokugamage et al, 2020) and may have lost their anti-interferon functions. It could explain why SARS-CoV-2 displays in vitro a substantial sensitivity to IFNα (Lokugamage et al, 2020): although SARS-CoV-2 replication is not entirely suppressed by interferons, viral titers are decreased by several orders of magnitude.…”

“…However, the Orf6 and Orf3b proteins of SARS-CoV-2 are truncated (Lokugamage et al, 2020) and may have lost their anti-interferon functions. It could explain why SARS-CoV-2 displays in vitro a substantial sensitivity to IFNα (Lokugamage et al, 2020): although SARS-CoV-2 replication is not entirely suppressed by interferons, viral titers are decreased by several orders of magnitude. SARS-CoV2 is substantially more sensitive to IFN-I than SARS-CoV, which suggests that IFN-I treatment should be at least as effective for the former than for the latter.…”

“…The combination of IFN-I with lopinavir/ritonavir, ribavirin or remdesivir could improve its efficacy, because of the efficiency of such combinations observed in vitro in other coronaviruses (Sheahan et al, 2020). It might also be relevant to evaluate type III IFN for the treatment of COVID-19 (Lokugamage et al, 2020), because of the protective effects of this interferon type in the respiratory tract. Subcutaneous IFNβ1a in combination with lopinavir/ritonavir is compared to lopinavir/ritonavir alone, hydroxychloroquine, and remdesivir in the DisCoVeRy trial (NCT04315948), which is the first clinical trial of the WHO Solidarity consortium of clinical trials.…”

An Infectious cDNA Clone of SARS-CoV-2

“…To explore the utility of icSARS-CoV-2-mNG, we used the reporter virus to rapidly screen the antiviral activity of a known inhibitor of coronaviruses. We previously showed that pre-treatment of Vero cells with type 1 IFN inhibits SARS-CoV-2 replication (Lokugamage et al, 2020). Here, we explored the doseresponsive effect of IFN-a pre-treatment on icSARS-CoV-mNG replication ( Figure 4C).…”