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. HuangCatherine Schuster, Koichi Watashi, Timothy S.C. Hinks, Aarti Jagannath, Sridhar R. Vausdevan, Dalan Bailey, Thomas F. Baumert, Jane A. McKeating*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

34 Scopus citations

Abstract

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.

Original languageEnglish
Article number103144
JournaliScience
Volume24
Issue number10
DOIs
StatePublished - 22 10 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Keywords

  • Microbiology
  • Molecular biology
  • Transcriptomics
  • Virology

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