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Hypoxic and pharmacological activation of HIFs inhibits SARS-CoV-2 infection of lung epithelial cells
- Source :
- Cell Reports, Cell Reports, Vol 35, Iss 3, Pp 109020-(2021)
- Publication Year :
- 2021
- Publisher :
- Cell Press, 2021.
-
Abstract
- COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment and one important factor to consider is oxygen tension, where hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its Spike glycoprotein binding to angiotensin-converting enzyme (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via a HIF-1α dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication showing that post-entry steps in the viral life cycle are oxygen-sensitive. This study highlights the importance of HIF signalling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19.<br />Graphical Abstract<br />Wing et al. demonstrate that key aspects of the SARS-CoV-2 life cycle are dependent on cellular oxygen tension. Activation of the cellular oxygen sensing pathway inhibits SARS-CoV-2 infection, highlighting a key cellular pathway that could be exploited as a potential therapeutic avenue for COVID-19.
- Subjects :
- 0301 basic medicine
QH301-705.5
viruses
Glycine
Biology
Virus Replication
medicine.disease_cause
General Biochemistry, Genetics and Molecular Biology
Mice
03 medical and health sciences
0302 clinical medicine
Report
Chlorocebus aethiops
medicine
Animals
Humans
Biology (General)
Lung
Vero Cells
Coronavirus
A549 cell
Glycoprotein binding
SARS-CoV-2
COVID-19
Epithelial Cells
HIF prolyl-hydroxylase inhibitor
Virus Internalization
Hypoxia (medical)
Hypoxia-Inducible Factor 1, alpha Subunit
Isoquinolines
Cell Hypoxia
COVID-19 Drug Treatment
Cell biology
Oxygen tension
030104 developmental biology
Viral replication
Hypoxia-inducible factors
A549 Cells
hypoxia, HIF, SARS-CoV-2, HIF prolyl hydroxylase inhibitor
Caco-2 Cells
medicine.symptom
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....dd8e53769facfdeba33434aaf01a539d