SARS-CoV-2 Nsp2 Contributes to Inflammation by Activating NF-κB

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• COVID-19 is characterized by significant inflammation and compromised antiviral immunity.
• The precise mechanisms by which SARS-CoV-2 influences inflammatory gene expression remain incompletely understood.

Purpose of the Study:

• To investigate the inflammatory and antiviral responses during SARS-CoV-2 infection.
• To elucidate the role of SARS-CoV-2 non-structural protein 2 (Nsp2) in modulating host immune responses.

Main Methods:

• Infection of K18-hACE2 mice with a Wuhan-like SARS-CoV-2 strain.
• Analysis of interferon (IFN), cytokine, and chemokine expression in mouse lung homogenates.
• Assessment of IFNβ expression and NF-κB activation in human pulmonary cells upon SARS-CoV-2 infection and Nsp2 expression.

Main Results:

• SARS-CoV-2 infection induced pro-inflammatory chemokines via NF-κB activation but showed weak induction of IL1β and IL18, alongside downregulated inflammasome effectors.
• Infection of human cells with SARS-CoV-2 robustly activated the NF-κB p65 subunit.
• SARS-CoV-2 Nsp2 expression activated the IFNβ promoter through its NF-κB regulatory domain and promoted p65 phosphorylation.

Conclusions:

• SARS-CoV-2 infection skews the host's antiviral response towards an NF-κB-driven inflammatory signature, characteristic of acute COVID-19.
• The viral protein Nsp2 is identified as a significant contributor to this SARS-CoV-2-induced inflammatory response.