Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling

Area of Science:

• Virology
• Immunology
• Drug Discovery

Background:

• SARS-CoV-2 replication relies on host cell machinery.
• Cyclosporine A (CsA), an immunosuppressant, shows pan-coronavirus inhibitory potential, but its mechanism against SARS-CoV-2 is unclear.
• Nsp1 is a key SARS-CoV-2 protein that manipulates host cell pathways.

Purpose of the Study:

• To elucidate the molecular mechanism by which CsA inhibits SARS-CoV-2 replication.
• To identify the roles of host factors DDX5 and NFAT signaling in SARS-CoV-2 pathogenesis.
• To validate calcineurin inhibitors as potential antiviral agents against SARS-CoV-2.

Main Methods:

• Investigated the interaction between SARS-CoV-2 Nsp1 and host cell proteins.
• Utilized Nsp1-deficient mutant viruses to assess viral replication.
• Assessed the antiviral effects of calcineurin inhibitors alone and in combination with nirmatrelvir.

Main Results:

• SARS-CoV-2 Nsp1 hijacks calcineurin-NFAT signaling to induce DDX5 expression, facilitating viral replication.
• Nsp1 displaces RCAN3 from calcineurin A, leading to NFAT activation.
• Calcineurin inhibitors (CsA, VIVIT) effectively inhibited SARS-CoV-2 replication.
• Combination therapy with CsA or VIVIT and nirmatrelvir showed synergistic antiviral effects.

Conclusions:

• Delineated the mechanism of CsA-mediated SARS-CoV-2 inhibition involving Nsp1, NFAT, and DDX5.
• Calcineurin inhibitors represent a promising therapeutic strategy against SARS-CoV-2.
• Combined use of calcineurin inhibitors with nirmatrelvir enhances antiviral efficacy.