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

Zhuang, X.; Tsukuda, S.; Wrensch, F.; Wing, P. A.; Borrmann, H.; Harris, J. M.; Morgan, S. B.; Mailly, L.; Thakur, N.; Conceicao, C.; Sanghani, H.; Heydmann, L.; Bach, C.; Ashton, A.; Walsh, S.; Tan, T. K.; Schimanski, L.; Huang, K.-Y. A.; Schuster, C.; Watashi, K.; Hinks, T. S.; Jagannath, A.; Vausdevan, S. R.; Bailey, D.; Baumert, T. F.; McKeating, J. A.

doi:10.1101/2021.03.20.436163

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bioRxiv · 10.1101/2021.03.20.436163

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

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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 Spike glycoprotein binding angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organisms response to its environment and can regulate host susceptibility to virus infection. We demonstrate a circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with a synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry. 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. Transcriptome analysis revealed that Bmal1 silencing induced a wide spectrum of interferon stimulated genes in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to dampen SARS-CoV-2 infection. Our study suggests new approaches to understand and improve therapeutic targeting of SARS-CoV-2.

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Zhuang, X., Tsukuda, S., Wrensch, F., Wing, P. A., Borrmann, H., Harris, J. M., Morgan, S. B., Mailly, L., Thakur, N., Conceicao, C., Sanghani, H., Heydmann, L., Bach, C., Ashton, A., Walsh, S., Tan, T. K., Schimanski, L., Huang, K.-Y. A., Schuster, C., Watashi, K., Hinks, T. S., Jagannath, A., Vausdevan, S. R., Bailey, D., Baumert, T. F., McKeating, J. A.. 2021-03-21. Circadian regulation of SARS-CoV-2 infection in lung epithelial cells. https://doi.org/10.1101/2021.03.20.436163

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