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SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial derived cells and cardiomyocytes.
bioRxiv ; 2020 Nov 02.
Article in English | MEDLINE | ID: covidwho-808974
Preprint
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
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LOCATION_OF
Object
C5203676
3. Epithelial Cells PART_OF Nose
Subject
Epithelial Cells
Predicate
PART_OF
Object
Nose
4. Interferons STIMULATES EIF2AK2 protei
Subject
Interferons
Predicate
STIMULATES
Object
EIF2AK2 protei
5. 2-5A-dependent ribonuclease STIMULATES EIF2AK2 protei
Subject
2-5A-dependent ribonuclease
Predicate
STIMULATES
Object
EIF2AK2 protei
6. A549 Cells LOCATION_OF Increased DNA Replication
Subject
A549 Cells
Predicate
LOCATION_OF
Object
Increased DNA Replication
7. Epithelial Cells LOCATION_OF 2019 novel coronavirus
Subject
Epithelial Cells
Predicate
LOCATION_OF
Object
2019 novel coronavirus
8. Myocytes, Cardiac LOCATION_OF 2019 novel coronavirus
Subject
Myocytes, Cardiac
Predicate
LOCATION_OF
Object
2019 novel coronavirus
9. Epithelial Cells PART_OF Nose
Subject
Epithelial Cells
Predicate
PART_OF
Object
Nose
10. Interferons STIMULATES EIF2AK2 protein, human|EIF2AK2
Subject
Interferons
Predicate
STIMULATES
Object
EIF2AK2 protein, human|EIF2AK2
11. 2-5A-dependent ribonuclease STIMULATES EIF2AK2 protein, human|EIF2AK2
Subject
2-5A-dependent ribonuclease
Predicate
STIMULATES
Object
EIF2AK2 protein, human|EIF2AK2
12. 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, while PKR activation is evident in iAT2 and iCM. In SARS-CoV-2 infected Calu-3 and A549 ACE2 lung-derived cell lines, IFN induction remains relatively weak; however activation of OAS-RNase L and PKR is observed. This is in contrast to MERS-CoV, which effectively inhibits IFN signaling as well as OAS-RNase L and PKR pathways, but similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, both OAS-RNase L and PKR are activated in MAVS knockout A549 ACE2 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 A549 ACE2 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.

SIGNIFICANCE:

SARS-CoV-2 emergence in late 2019 led to the COVID-19 pandemic that has had devastating effects on human health and the economy. Early innate immune responses are essential for protection against virus invasion. While inadequate innate immune responses are associated with severe COVID-19 diseases, understanding of the interaction of SARS-CoV-2 with host antiviral pathways is minimal. We have characterized the innate immune response to SARS-CoV-2 infections in relevant respiratory tract derived cells and cardiomyocytes and found that SARS-CoV-2 activates two antiviral pathways, oligoadenylate synthetase-ribonuclease L (OAS-RNase L), and protein kinase R (PKR), while inducing minimal levels of interferon. This in contrast to MERS-CoV which inhibits all three pathways. Activation of these pathways may contribute to the distinctive pathogenesis of SARS-CoV-2.

Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2020 Document Type: Article

Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2020 Document Type: Article