MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells

Cell Rep. 2021 Jan 12;34(2):108628. doi: 10.1016/j.celrep.2020.108628.


Recent studies have profiled the innate immune signatures in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suggest that cellular responses to viral challenge may affect disease severity. Yet the molecular events that underlie cellular recognition and response to SARS-CoV-2 infection remain to be elucidated. Here, we find that SARS-CoV-2 replication induces a delayed interferon (IFN) response in lung epithelial cells. By screening 16 putative sensors involved in sensing of RNA virus infection, we found that MDA5 and LGP2 primarily regulate IFN induction in response to SARS-CoV-2 infection. Further analyses revealed that viral intermediates specifically activate the IFN response through MDA5-mediated sensing. Additionally, we find that IRF3, IRF5, and NF-κB/p65 are the key transcription factors regulating the IFN response during SARS-CoV-2 infection. In summary, these findings provide critical insights into the molecular basis of the innate immune recognition and signaling response to SARS-CoV-2.

Keywords: IRF3; IRF5; MDA5; NF-κB/p65; SARS-CoV-2; interferon; lung epithelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 / pathology
  • COVID-19 / virology
  • Cell Line
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology
  • Epithelial Cells / virology
  • Humans
  • Immunity, Innate*
  • Induced Pluripotent Stem Cells / cytology
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Interferon-Induced Helicase, IFIH1 / metabolism*
  • Interferons / genetics
  • Interferons / metabolism
  • RNA Helicases / metabolism
  • RNA Interference
  • RNA, Double-Stranded / metabolism
  • RNA, Small Interfering / metabolism
  • SARS-CoV-2 / immunology
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / physiology*
  • Signal Transduction
  • Transcription Factor RelA / metabolism
  • Virus Replication


  • IRF3 protein, human
  • IRF5 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factors
  • RNA, Double-Stranded
  • RNA, Small Interfering
  • Transcription Factor RelA
  • Interferons
  • DHX58 protein, human
  • IFIH1 protein, human
  • Interferon-Induced Helicase, IFIH1
  • RNA Helicases