SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes
Copyright © 2021 the Author(s). Published by PNAS..
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 A549ACE2 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 MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:118 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 118(2021), 16 vom: 20. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Yize [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.04.2021 Date Revised 12.07.2023 published: Print UpdateOf: bioRxiv. 2020 Nov 02;:. - PMID 32995797 Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2022643118 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM323666663 |
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| 100 | 1 | |a Li, Yize |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 13.04.2021 | ||
| 500 | |a Date Revised 12.07.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a UpdateOf: bioRxiv. 2020 Nov 02;:. - PMID 32995797 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 the Author(s). Published by PNAS. | ||
| 520 | |a 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 A549ACE2 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 MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 650 | 7 | |a Endoribonucleases |2 NLM | |
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| 700 | 1 | |a Renner, David M |e verfasserin |4 aut | |
| 700 | 1 | |a Comar, Courtney E |e verfasserin |4 aut | |
| 700 | 1 | |a Whelan, Jillian N |e verfasserin |4 aut | |
| 700 | 1 | |a Reyes, Hanako M |e verfasserin |4 aut | |
| 700 | 1 | |a Cardenas-Diaz, Fabian Leonardo |e verfasserin |4 aut | |
| 700 | 1 | |a Truitt, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Li Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Beihua |e verfasserin |4 aut | |
| 700 | 1 | |a Alysandratos, Konstantinos Dionysios |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Jessie |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, James N |e verfasserin |4 aut | |
| 700 | 1 | |a Adappa, Nithin D |e verfasserin |4 aut | |
| 700 | 1 | |a Kohanski, Michael A |e verfasserin |4 aut | |
| 700 | 1 | |a Kotton, Darrell N |e verfasserin |4 aut | |
| 700 | 1 | |a Silverman, Robert H |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Wenli |e verfasserin |4 aut | |
| 700 | 1 | |a Morrisey, Edward E |e verfasserin |4 aut | |
| 700 | 1 | |a Cohen, Noam A |e verfasserin |4 aut | |
| 700 | 1 | |a Weiss, Susan R |e verfasserin |4 aut | |
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