iScience (Oct 2021)
The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells
- Xiaodong Zhuang,
- Senko Tsukuda,
- Florian Wrensch,
- Peter A.C. Wing,
- Mirjam Schilling,
- James M. Harris,
- Helene Borrmann,
- Sophie B. Morgan,
- Jennifer L. Cane,
- Laurent Mailly,
- Nazia Thakur,
- Carina Conceicao,
- Harshmeena Sanghani,
- Laura Heydmann,
- Charlotte Bach,
- Anna Ashton,
- Steven Walsh,
- Tiong Kit Tan,
- Lisa Schimanski,
- Kuan-Ying A. Huang,
- Catherine Schuster,
- Koichi Watashi,
- Timothy S.C. Hinks,
- Aarti Jagannath,
- Sridhar R. Vausdevan,
- Dalan Bailey,
- Thomas F. Baumert,
- Jane A. McKeating
Affiliations
- Xiaodong Zhuang
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Senko Tsukuda
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Florian Wrensch
- Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- 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
- Mirjam Schilling
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- James M. Harris
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Helene Borrmann
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Sophie B. Morgan
- Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine, Experimental Medicine, University of Oxford, UK
- Jennifer L. Cane
- Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine, Experimental Medicine, University of Oxford, UK
- Laurent Mailly
- Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Nazia Thakur
- The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, UK
- Carina Conceicao
- The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, UK
- Harshmeena Sanghani
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Laura Heydmann
- Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Charlotte Bach
- Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Anna Ashton
- Department of Pharmacology, University of Oxford, Oxford, UK
- Steven Walsh
- Department of Pharmacology, University of Oxford, Oxford, UK
- Tiong Kit Tan
- MRC Human Immunology Unit, MRC Weatherall Institute, John Radcliffe Hospital, Oxford 17 OX3 9DS, UK
- Lisa Schimanski
- Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; MRC Human Immunology Unit, MRC Weatherall Institute, John Radcliffe Hospital, Oxford 17 OX3 9DS, UK
- Kuan-Ying A. Huang
- Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University and Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Catherine Schuster
- Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- 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
- Timothy S.C. Hinks
- Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine, Experimental Medicine, University of Oxford, UK
- Aarti Jagannath
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Sridhar R. Vausdevan
- Department of Pharmacology, University of Oxford, Oxford, UK
- Dalan Bailey
- The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, UK
- Thomas F. Baumert
- Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Pole Hépato-digestif, IHU, Hopitaux Universitaires de Strasbourg, Strasbourg, France
- 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
- Journal volume & issue
-
Vol. 24,
no. 10
p. 103144
Abstract
Summary: The coronavirus disease 2019 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract via spike glycoprotein binding to angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organism's response to its environment and can regulate host susceptibility to virus infection. We demonstrate that silencing the circadian regulator Bmal1 or treating lung epithelial cells with the REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and replication. Importantly, treating infected cells with SR9009 limits SARS-CoV-2 replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced interferon-stimulated gene transcripts in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to limit SARS-CoV-2 infection. Our study highlights alternative approaches to understand and improve therapeutic targeting of SARS-CoV-2.
