Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells
Peter A.C. Wing,
Thomas P. Keeley,
Xiaodong Zhuang,
Jeffrey Y. Lee,
Maria Prange-Barczynska,
Senko Tsukuda,
Sophie B. Morgan,
Adam C. Harding,
Isobel L.A. Argles,
Samvid Kurlekar,
Marko Noerenberg,
Craig P. Thompson,
Kuan-Ying A. Huang,
Peter Balfe,
Koichi Watashi,
Alfredo Castello,
Timothy S.C. Hinks,
William James,
Peter J. Ratcliffe,
Ilan Davis,
Emma J. Hodson,
Tammie Bishop,
Jane A. McKeating
Affiliations
Peter A.C. Wing
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
Thomas P. Keeley
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
Xiaodong Zhuang
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Jeffrey Y. Lee
Department of Biochemistry, University of Oxford, Oxford, UK
Maria Prange-Barczynska
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
Senko Tsukuda
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Sophie B. Morgan
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
Adam C. Harding
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Isobel L.A. Argles
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Samvid Kurlekar
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Marko Noerenberg
Department of Biochemistry, University of Oxford, Oxford, UK; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
Craig P. Thompson
Peter Medawar Building for Pathogen Research, Department of Zoology, University of Oxford, Oxford, UK
Kuan-Ying A. Huang
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
Peter Balfe
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Koichi Watashi
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
Alfredo Castello
Department of Biochemistry, University of Oxford, Oxford, UK; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
Timothy S.C. Hinks
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
William James
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Peter J. Ratcliffe
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK; Francis Crick Institute, London, UK
Ilan Davis
Department of Biochemistry, University of Oxford, Oxford, UK
Emma J. Hodson
Francis Crick Institute, London, UK; Department of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK
Tammie Bishop
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
Jane A. McKeating
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; Corresponding author
Summary: 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.
