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

doi:10.1016/j.celrep.2020.108628

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

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

266 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 language	English (US)
Article number	108628
Journal	Cell reports
Volume	34
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2020.108628
State	Published - Jan 12 2021

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2020.108628

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Yin, X., Riva, L., Pu, Y., Martin-Sancho, L., Kanamune, J., Yamamoto, Y., Sakai, K., Gotoh, S., Miorin, L., De Jesus, P. D., Yang, C. C., Herbert, K. M., Yoh, S., Hultquist, J. F., García-Sastre, A., & Chanda, S. K. (2021). MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells. Cell reports, 34(2), Article 108628. https://doi.org/10.1016/j.celrep.2020.108628

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title = "MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells",

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.",

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author = "Xin Yin and Laura Riva and Yuan Pu and Laura Martin-Sancho and Jun Kanamune and Yuki Yamamoto and Kouji Sakai and Shimpei Gotoh and Lisa Miorin and {De Jesus}, {Paul D.} and Yang, {Chih Cheng} and Herbert, {Kristina M.} and Sunnie Yoh and Hultquist, {Judd F.} and Adolfo Garc{\'i}a-Sastre and Chanda, {Sumit K.}",

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AU - Yin, Xin

AU - Riva, Laura

AU - Pu, Yuan

AU - Martin-Sancho, Laura

AU - Kanamune, Jun

AU - Yamamoto, Yuki

AU - Sakai, Kouji

AU - Gotoh, Shimpei

AU - Miorin, Lisa

AU - De Jesus, Paul D.

AU - Yang, Chih Cheng

AU - Herbert, Kristina M.

AU - Yoh, Sunnie

AU - Hultquist, Judd F.

AU - García-Sastre, Adolfo

AU - Chanda, Sumit K.

PY - 2021/1/12

Y1 - 2021/1/12

N2 - 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.

AB - 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.

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

Abstract

Keywords

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