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SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes.
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.
  • Li Y; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104; weisssr@pennmedicine.upenn.edu yizelee@gmail.com.
  • Renner DM; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Comar CE; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Whelan JN; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Reyes HM; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Cardenas-Diaz FL; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Truitt R; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Tan LH; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Dong B; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Alysandratos KD; Penn Center for Research on Coronaviruses and Other Emerging Pathogens, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Huang J; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Palmer JN; Penn-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Adappa ND; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Kohanski MA; Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Kotton DN; Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Silverman RH; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
  • Yang W; Department of Medicine, The Pulmonary Center, Center for Regenerative Medicine, Boston University School of Medicine, Boston, MA 02118.
  • Morrisey EE; Department of Medicine, The Pulmonary Center, Center for Regenerative Medicine, Boston University School of Medicine, Boston, MA 02118.
  • Cohen NA; Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
  • Weiss SR; Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A ; 118(16)2021 04 20.
Article in English | MEDLINE | ID: covidwho-1165017
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This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
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Semantic information from SemMedBD (by NLM)
1. Epithelial Cells LOCATION_OF 2019 novel coronavirus
Subject
Epithelial Cells
Predicate
LOCATION_OF
Object
2019 novel coronavirus
2. Myocyte LOCATION_OF C5203676
Subject
Myocyte
Predicate
LOCATION_OF
Object
C5203676
3. Response process ASSOCIATED_WITH Coronavirus Infections
Subject
Response process
Predicate
ASSOCIATED_WITH
Object
Coronavirus Infections
4. Epithelial Cells PART_OF Nose
Subject
Epithelial Cells
Predicate
PART_OF
Object
Nose
5. Lung LOCATION_OF 2019 novel coronavirus
Subject
Lung
Predicate
LOCATION_OF
Object
2019 novel coronavirus
6. Site LOCATION_OF Epithelial Cells
Subject
Site
Predicate
LOCATION_OF
Object
Epithelial Cells
7. Cells NEG_LOCATION_OF IFNA1
Subject
Cells
Predicate
NEG_LOCATION_OF
Object
IFNA1
8. Cells NEG_LOCATION_OF 2-5A-dependent ribonuclease
Subject
Cells
Predicate
NEG_LOCATION_OF
Object
2-5A-dependent ribonuclease
9. 2-5A-dependent ribonuclease STIMULATES IFNA1
Subject
2-5A-dependent ribonuclease
Predicate
STIMULATES
Object
IFNA1
10. protein kinase R STIMULATES IFNA1
Subject
protein kinase R
Predicate
STIMULATES
Object
IFNA1
11. IFNA1 DISRUPTS Immune
Subject
IFNA1
Predicate
DISRUPTS
Object
Immune
12. 2-5A-dependent ribonuclease DISRUPTS Immune
Subject
2-5A-dependent ribonuclease
Predicate
DISRUPTS
Object
Immune
13. protein kinase R DISRUPTS Immune
Subject
protein kinase R
Predicate
DISRUPTS
Object
Immune
14. 2-5A-dependent ribonuclease STIMULATES A549 Cells
Subject
2-5A-dependent ribonuclease
Predicate
STIMULATES
Object
A549 Cells
15. protein kinase R STIMULATES A549 Cells
Subject
protein kinase R
Predicate
STIMULATES
Object
A549 Cells
16. A549 Cells LOCATION_OF Increased DNA Replication
Subject
A549 Cells
Predicate
LOCATION_OF
Object
Increased DNA Replication
17. Epithelial Cells LOCATION_OF 2019 novel coronavirus
Subject
Epithelial Cells
Predicate
LOCATION_OF
Object
2019 novel coronavirus
18. Myocytes, Cardiac LOCATION_OF 2019 novel coronavirus
Subject
Myocytes, Cardiac
Predicate
LOCATION_OF
Object
2019 novel coronavirus
19. Response process ASSOCIATED_WITH Coronavirus Infections
Subject
Response process
Predicate
ASSOCIATED_WITH
Object
Coronavirus Infections
20. Epithelial Cells PART_OF Nose
Subject
Epithelial Cells
Predicate
PART_OF
Object
Nose
21. Lung LOCATION_OF 2019 novel coronavirus
Subject
Lung
Predicate
LOCATION_OF
Object
2019 novel coronavirus
22. Site LOCATION_OF Epithelial Cells
Subject
Site
Predicate
LOCATION_OF
Object
Epithelial Cells
23. Cells NEG_LOCATION_OF IFNA1
Subject
Cells
Predicate
NEG_LOCATION_OF
Object
IFNA1
24. Cells NEG_LOCATION_OF 2-5A-dependent ribonuclease
Subject
Cells
Predicate
NEG_LOCATION_OF
Object
2-5A-dependent ribonuclease
25. 2-5A-dependent ribonuclease STIMULATES IFNA1
Subject
2-5A-dependent ribonuclease
Predicate
STIMULATES
Object
IFNA1
26. protein kinase R STIMULATES IFNA1
Subject
protein kinase R
Predicate
STIMULATES
Object
IFNA1
27. IFNA1 DISRUPTS Immune
Subject
IFNA1
Predicate
DISRUPTS
Object
Immune
28. 2-5A-dependent ribonuclease DISRUPTS Immune
Subject
2-5A-dependent ribonuclease
Predicate
DISRUPTS
Object
Immune
29. protein kinase R DISRUPTS Immune
Subject
protein kinase R
Predicate
DISRUPTS
Object
Immune
30. 2-5A-dependent ribonuclease STIMULATES A549 Cells
Subject
2-5A-dependent ribonuclease
Predicate
STIMULATES
Object
A549 Cells
31. protein kinase R STIMULATES A549 Cells
Subject
protein kinase R
Predicate
STIMULATES
Object
A549 Cells
32. A549 Cells LOCATION_OF Increased DNA Replication
Subject
A549 Cells
Predicate
LOCATION_OF
Object
Increased DNA Replication
ABSTRACT
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Double-Stranded / Myocytes, Cardiac / Epithelial Cells / SARS-CoV-2 / Immunity, Innate / Lung Limits: Humans Language: English Year: 2021 Document Type: Article

Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Double-Stranded / Myocytes, Cardiac / Epithelial Cells / SARS-CoV-2 / Immunity, Innate / Lung Limits: Humans Language: English Year: 2021 Document Type: Article