The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells
Zhuang X., Tsukuda S., Wrensch F., Wing PAC., Schilling M., Harris JM., Borrmann H., Morgan SB., Cane JL., Mailly L., Thakur N., Conceicao C., Sanghani H., Heydmann L., Bach C., Ashton A., Walsh S., Tan TK., Schimanski L., Huang K-YA., Schuster C., Watashi K., Hinks TSC., Jagannath A., Vausdevan SR., Bailey D., Baumert TF., McKeating JA.
SUMMARYThe 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 organism’s 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.