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Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells.
Wing, Peter A C; Keeley, Thomas P; Zhuang, Xiaodong; Lee, Jeffrey Y; Prange-Barczynska, Maria; Tsukuda, Senko; Morgan, Sophie B; Harding, Adam C; Argles, Isobel L A; Kurlekar, Samvid; Noerenberg, Marko; Thompson, Craig P; Huang, Kuan-Ying A; Balfe, Peter; Watashi, Koichi; Castello, Alfredo; Hinks, Timothy S C; James, William; Ratcliffe, Peter J; Davis, Ilan; Hodson, Emma J; Bishop, Tammie; McKeating, Jane A.
  • Wing PAC; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
  • Keeley TP; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Zhuang X; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Lee JY; Department of Biochemistry, University of Oxford, Oxford, UK.
  • Prange-Barczynska M; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Tsukuda S; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Morgan SB; 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.
  • Harding AC; Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • Argles ILA; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Kurlekar S; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Noerenberg M; Department of Biochemistry, University of Oxford, Oxford, UK; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
  • Thompson CP; Peter Medawar Building for Pathogen Research, Department of Zoology, University of Oxford, Oxford, UK.
  • Huang KA; 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.
  • Balfe P; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Watashi K; 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.
  • Castello A; Department of Biochemistry, University of Oxford, Oxford, UK; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
  • Hinks TSC; 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.
  • James W; Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • Ratcliffe PJ; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK; Francis Crick Institute, London, UK.
  • Davis I; Department of Biochemistry, University of Oxford, Oxford, UK.
  • Hodson EJ; Francis Crick Institute, London, UK; Department of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK.
  • Bishop T; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • McKeating JA; 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.
Cell Rep ; 35(3): 109020, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1182447
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Replication / Epithelial Cells / Hypoxia-Inducible Factor 1, alpha Subunit / Virus Internalization / SARS-CoV-2 / COVID-19 / Glycine / Isoquinolines / Lung Limits: Animals / Humans Language: English Journal: Cell Rep Year: 2021 Document Type: Article Affiliation country: J.celrep.2021.109020

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Replication / Epithelial Cells / Hypoxia-Inducible Factor 1, alpha Subunit / Virus Internalization / SARS-CoV-2 / COVID-19 / Glycine / Isoquinolines / Lung Limits: Animals / Humans Language: English Journal: Cell Rep Year: 2021 Document Type: Article Affiliation country: J.celrep.2021.109020