1. Hypoxic and pharmacological activation of HIFs inhibits SARS-CoV-2 infection of lung epithelial cells
- Author
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Ilan Davis, Peter J. Ratcliffe, Alfredo Castello, William James, Jeffrey Y. Lee, Maria Prange-Barczynska, Marko Noerenberg, Jane A. McKeating, Craig Thompson, Senko Tsukuda, Koichi Watashi, Isobel L.A. Argles, Thomas P. Keeley, Sophie B. Morgan, Peter A C Wing, Samvid Kurlekar, Kuan-Ying A. Huang, Xiaodong Zhuang, Timothy S. C. Hinks, Tammie Bishop, Peter Balfe, Emma J. Hodson, and Adam Harding
- 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 - 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., Graphical Abstract, 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.
- Published
- 2021