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SARS-CoV-2 Nonstructural Protein 1 Inhibits the Interferon Response by Causing Depletion of Key Host Signaling
Anil Kumar1, Ray Ishida2, Tania Strilets2
1Department of Cell Biology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada.
Journal of Virology
|June 10, 2021
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades the interferon (IFN) response using novel mechanisms. SARS-CoV-2 nonstructural protein 1 (NSP1) blocks IFN induction and signaling, aiding viral infection.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the COVID-19 pandemic.
- SARS-CoV-2 antagonizes the interferon (IFN) response, but mechanisms remain unclear.
Purpose of the Study:
- To elucidate novel mechanisms by which SARS-CoV-2 inhibits the IFN pathway.
- To identify specific viral proteins involved in blocking IFN induction and signaling.
Main Methods:
- Assessing IFN and IFN-stimulated gene (ISG) induction in SARS-CoV-2 infected cells.
- Quantifying Tyk2 and STAT2 levels in infected cells.
- Expressing SARS-CoV-2 nonstructural protein 1 (NSP1) and nucleocapsid individually to assess their impact on IFN pathways.
- Mapping studies to identify the molecular targets of NSP1.
Main Results:
- Type I IFNs and ISGs were poorly induced during SARS-CoV-2 infection.
- Tyk2 and STAT2 levels were significantly reduced in infected cells.
- NSP1 blocked IFN induction by inhibiting IRF3 phosphorylation and dampened ISG induction by depleting Tyk2 and STAT2.
- Nucleocapsid also blocked IFN induction, but NSP1 was the primary inhibitor of IFN signaling.
Conclusions:
- SARS-CoV-2 employs novel mechanisms, primarily involving NSP1, to evade the host IFN response.
- NSP1's ability to block IRF3 phosphorylation and deplete Tyk2/STAT2 is crucial for SARS-CoV-2's immune evasion.
- Understanding these mechanisms is vital for developing effective therapeutics against SARS-CoV-2.
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