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
Affiliations
Xin Yin
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, P.R. China
Laura Riva
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Yuan Pu
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Laura Martin-Sancho
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Jun Kanamune
Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Yuki Yamamoto
Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Kouji Sakai
Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Shimpei Gotoh
Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
Lisa Miorin
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Paul D. De Jesus
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Chih-Cheng Yang
Functional Genomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Kristina M. Herbert
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Sunnie Yoh
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Judd F. Hultquist
Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL 60201, USA
Adolfo García-Sastre
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Sumit K. Chanda
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: 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.
