SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes

Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe c...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2021-04, Vol.118 (16), p.1
Main Authors: Li, Yize, Renner, David M, Comar, Courtney E, Whelan, Jillian N, Reyes, Hanako M, Cardenas-Diaz, Fabian Leonardo, Truitt, Rachel, Tan, Li Hui, Dong, Beihua, Alysandratos, Konstantinos Dionysios, Huang, Jessie, Palmer, James N, Adappa, Nithin D, Kohanski, Michael A, Kotton, Darrell N, Silverman, Robert H, Yang, Wenli, Morrisey, Edward E, Cohen, Noam A, Weiss, Susan R
Format: Article
Language:English
Subjects:
A549 Cells
Alveoli
Antagonists
Biological Sciences
Cardiomyocytes
Cell activation
Cell lines
Coronaviridae
Coronaviruses
COVID-19
Double-stranded RNA
eIF-2 Kinase
Endoribonucleases - metabolism
Epithelial cells
Epithelial Cells - immunology
Epithelial Cells - virology
Epithelium
Humans
Immune response
Immunity, Innate
Infections
Innate immunity
Interferon
Kinases
Lung - pathology
Lungs
Middle East respiratory syndrome
Middle East Respiratory Syndrome Coronavirus - immunology
Middle East Respiratory Syndrome Coronavirus - physiology
Myocytes, Cardiac - immunology
Myocytes, Cardiac - virology
Nose - virology
Pathogenesis
Pluripotency
Protein kinase R
Respiratory diseases
Ribonuclease L
RNA, Double-Stranded - metabolism
SARS-CoV-2 - immunology
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Signal transduction
Signaling
Stem cells
Viral diseases
Virus Replication
Viruses
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Summary:Coronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection; induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung; and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, whereas PKR activation is evident in iAT2 and iCM. In SARS-CoV-2-infected Calu-3 and A549 lung-derived cell lines, IFN induction remains relatively weak; however, activation of OAS-RNase L and PKR is observed. This is in contrast to Middle East respiratory syndrome (MERS)-CoV, which effectively inhibits IFN signaling and OAS-RNase L and PKR pathways, but is similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, OAS-RNase L and PKR are activated in knockout A549 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in knockout A549 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2022643118