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

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.
Competing Interests: Declaration of Interests The García-Sastre laboratory has received research support from Pfizer, Senhwa Biosciences, 7Hills Pharma, Pharmamar, Blade Therapeutics, Avimex, Dynavax, Kenall Manufacturing, and ImmunityBio. A.G.-S. has consulting agreements with the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Vaxalto, Accurius, and Esperovax. Y.Y. and S.G. are founders, shareholders, and board members of HiLung Inc. Y.Y. and S.G. have patents (PCT/JP2016/059786) related to this work.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)