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Circadian regulation of SARS-CoV-2 infection in lung epithelial cells

View ORCID ProfileXiaodong Zhuang, Senko Tsukuda, Florian Wrensch, Peter AC Wing, Helene Borrmann, James M Harris, Sophie B Morgan, 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 SC Hinks, Aarti Jagannath, Sridhar R Vausdevan, Dalan Bailey, Thomas F Baumert, View ORCID ProfileJane A McKeating
doi: https://doi.org/10.1101/2021.03.20.436163
Xiaodong Zhuang
1Nuffield Department of Medicine, University of Oxford, Oxford, UK
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Senko Tsukuda
1Nuffield Department of Medicine, University of Oxford, Oxford, UK
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Florian Wrensch
2Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
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Peter AC Wing
1Nuffield Department of Medicine, University of Oxford, Oxford, UK
3Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
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Helene Borrmann
1Nuffield Department of Medicine, University of Oxford, Oxford, UK
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James M Harris
1Nuffield Department of Medicine, University of Oxford, Oxford, UK
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Sophie B Morgan
4Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine, Experimental Medicine, University of Oxford, UK
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Laurent Mailly
2Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
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Nazia Thakur
5The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, UK
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Carina Conceicao
5The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, UK
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Harshmeena Sanghani
6Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
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Laura Heydmann
2Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
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Charlotte Bach
2Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
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Anna Ashton
7Department of Pharmacology, University of Oxford, Oxford, UK
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Steven Walsh
7Department of Pharmacology, University of Oxford, Oxford, UK
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Tiong Kit Tan
8MRC Human Immunology Unit, MRC Weatherall Institute, John Radcliffe Hospital, Oxford 17 OX3 9DS, UK
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Lisa Schimanski
3Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
8MRC Human Immunology Unit, MRC Weatherall Institute, John Radcliffe Hospital, Oxford 17 OX3 9DS, UK
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Kuan-Ying A Huang
9Research 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
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Catherine Schuster
2Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
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Koichi Watashi
10Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
11Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
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Timothy SC Hinks
4Respiratory Medicine Unit and National Institute for Health Research Oxford Biomedical Research Centre, Nuffield Department of Medicine, Experimental Medicine, University of Oxford, UK
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Aarti Jagannath
6Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
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Sridhar R Vausdevan
7Department of Pharmacology, University of Oxford, Oxford, UK
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Dalan Bailey
5The Pirbright Institute, Ash Road, Pirbright, Woking, Surrey, UK
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Thomas F Baumert
2Université de Strasbourg, Strasbourg, France and INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
12Pole Hépato-digestif, IHU, Hopitaux Universitaires de Strasbourg, Strasbourg, France
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Jane A McKeating
1Nuffield Department of Medicine, University of Oxford, Oxford, UK
3Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
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  • ORCID record for Jane A McKeating
  • For correspondence: jane.mckeating@ndm.ox.ac.uk
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ABSTRACT

The COVID-19 pandemic, caused by 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 binding human angiotensin-converting enzyme (ACE2)1,2, and infection can result in pneumonia and acute respiratory dist ress syndrome. Circadian rhythms coordinate an organisms response to its environment and recent studies report a role for the circadian clock to regulate host susceptibility to virus infection3. Influenza A infection of arhythmic mice, lacking the circadian component BMAL1, results in higher viral replication4 and elevated inflammatory responses leading to more severe bronchitis5,6, highlighting the impact of circadian pathways in respiratory function. We demonstrate circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with the synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and RNA replication. Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Our study suggests new approaches to understand and improve therapeutic targeting of COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* Shared first authorship

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 21, 2021.
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Circadian regulation of SARS-CoV-2 infection in lung epithelial cells
Xiaodong Zhuang, Senko Tsukuda, Florian Wrensch, Peter AC Wing, Helene Borrmann, James M Harris, Sophie B Morgan, 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 SC Hinks, Aarti Jagannath, Sridhar R Vausdevan, Dalan Bailey, Thomas F Baumert, Jane A McKeating
bioRxiv 2021.03.20.436163; doi: https://doi.org/10.1101/2021.03.20.436163
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Circadian regulation of SARS-CoV-2 infection in lung epithelial cells
Xiaodong Zhuang, Senko Tsukuda, Florian Wrensch, Peter AC Wing, Helene Borrmann, James M Harris, Sophie B Morgan, 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 SC Hinks, Aarti Jagannath, Sridhar R Vausdevan, Dalan Bailey, Thomas F Baumert, Jane A McKeating
bioRxiv 2021.03.20.436163; doi: https://doi.org/10.1101/2021.03.20.436163

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