RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells

Nat Immunol. 2021 Jul;22(7):820-828. doi: 10.1038/s41590-021-00942-0. Epub 2021 May 11.


Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity1,2. Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global pandemic. It is an urgent challenge to clarify the innate recognition mechanism to control this virus. Here we show that retinoic acid-inducible gene-I (RIG-I) sufficiently restrains SARS-CoV-2 replication in human lung cells in a type I/III interferon (IFN)-independent manner. RIG-I recognizes the 3' untranslated region of the SARS-CoV-2 RNA genome via the helicase domains, but not the C-terminal domain. This new mode of RIG-I recognition does not stimulate its ATPase, thereby aborting the activation of the conventional mitochondrial antiviral-signaling protein-dependent pathways, which is in accordance with lack of cytokine induction. Nevertheless, the interaction of RIG-I with the viral genome directly abrogates viral RNA-dependent RNA polymerase mediation of the first step of replication. Consistently, genetic ablation of RIG-I allows lung cells to produce viral particles that expressed the viral spike protein. By contrast, the anti-SARS-CoV-2 activity was restored by all-trans retinoic acid treatment through upregulation of RIG-I protein expression in primary lung cells derived from patients with chronic obstructive pulmonary disease. Thus, our findings demonstrate the distinctive role of RIG-I as a restraining factor in the early phase of SARS-CoV-2 infection in human lung cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • COVID-19 / immunology*
  • Cell Line
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • DEAD Box Protein 58 / immunology*
  • Dogs
  • HEK293 Cells
  • Humans
  • Interferon Lambda
  • Interferon Type I / immunology
  • Interferons / immunology
  • Lung / immunology*
  • Lung / virology
  • Madin Darby Canine Kidney Cells
  • Pulmonary Disease, Chronic Obstructive / immunology
  • RNA-Dependent RNA Polymerase / immunology
  • Receptors, Immunologic / immunology*
  • SARS-CoV-2 / immunology*
  • Sf9 Cells
  • Signal Transduction / immunology
  • Vero Cells
  • Viral Proteins / immunology


  • Interferon Type I
  • Receptors, Immunologic
  • Viral Proteins
  • Interferons
  • RNA-Dependent RNA Polymerase
  • DDX58 protein, human
  • DEAD Box Protein 58
  • Interferon Lambda