Circadian regulation of SARS-CoV-2 infection in lung epithelial cells.
Zhuang X., Tsukuda S., Wrensch F., Wing PA., Borrmann H., Harris JM., Morgan SB., 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 TS., Jagannath A., Vausdevan SR., Bailey D., Baumert TF., McKeating JA.
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 infection 3 . Influenza A infection of arhythmic mice, lacking the circadian component BMAL1, results in higher viral replication 4 and elevated inflammatory responses leading to more severe bronchitis 5,6 , 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.