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

Xin Yin, Laura Riva, Yuan Pu, Laura Martin-Sancho, Jun Kanamune, Yuki Yamamoto, Kouji Sakai, Shimpei Gotoh, Lisa Miorin, Paul D. De Jesus, Chih Cheng Yang, Kristina M. Herbert, Sunnie Yoh, Judd F. Hultquist, Adolfo García-Sastre, Sumit K. Chanda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number108628
JournalCell reports
Volume34
Issue number2
DOIs
StatePublished - Jan 12 2021

Keywords

  • IRF3
  • IRF5
  • MDA5
  • NF-κB/p65
  • SARS-CoV-2
  • interferon
  • lung epithelial cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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