2. Academic Validation
  3. Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells

Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells

  • Cell Rep. 2021 Apr 20;35(3):109020. doi: 10.1016/j.celrep.2021.109020.
Peter A C Wing 1,  Thomas P Keeley 2,  Xiaodong Zhuang 3,  Jeffrey Y Lee 4,  Maria Prange-Barczynska 2,  Senko Tsukuda 3,  Sophie B Morgan 5,  Adam C Harding 6,  Isobel L A Argles 3,  Samvid Kurlekar 3,  Marko Noerenberg 7,  Craig P Thompson 8,  Kuan-Ying A Huang 9,  Peter Balfe 3,  Koichi Watashi 10,  Alfredo Castello 7,  Timothy S C Hinks 5,  William James 6,  Peter J Ratcliffe 11,  Ilan Davis 4,  Emma J Hodson 12,  Tammie Bishop 2,  Jane A McKeating 13
Affiliations

Affiliations

  • 1 Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
  • 2 Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • 3 Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 4 Department of Biochemistry, University of Oxford, Oxford, UK.
  • 5 Respiratory Medicine Unit and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Nuffield Department of Medicine, Experimental Medicine, University of Oxford, Oxford, UK.
  • 6 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • 7 Department of Biochemistry, University of Oxford, Oxford, UK; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
  • 8 Peter Medawar Building for Pathogen Research, Department of Zoology, University of Oxford, Oxford, UK.
  • 9 Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • 10 Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan.
  • 11 Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK; Francis Crick Institute, London, UK.
  • 12 Francis Crick Institute, London, UK; Department of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK.
  • 13 Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. Electronic address: jane.mckeating@ndm.ox.ac.uk.
PMID: 33852916 DOI: 10.1016/j.celrep.2021.109020
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, in which 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 2 (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 an 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 signaling 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.

Keywords

hypoxia, HIF, SARS-CoV-2, HIF prolyl hydroxylase inhibitor.

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