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

Wai-Yin Lui1, Chon Phin Ong1, Pak-Hin Hinson Cheung1

  • 1School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.

Mbio
|February 27, 2024
PubMed

Insights

Cyclosporine A inhibits SARS-CoV-2 by targeting the viral Nsp1 protein, which interferes with NFAT signaling and DDX5 expression, crucial for viral replication. This reveals a new mechanism for calcineurin inhibitors against COVID-19.

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.
Keywords:
DDX5NFATNsp1RCAN3SARS-CoV-2calcineurin

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