The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells

Zhuang, Xiaodong; Tsukuda, Senko; Wrensch, Florian; Wing, Peter AC; Schilling, Mirjam; Harris, James M; Borrmann, Helene; Morgan, Sophie B; Cane, Jennifer L; Mailly, Laurent; Thakur, Nazia; Conceicao, Carina; Sanghani, Harshmeena; Heydmann, Laura; Bach, Charlotte; Ashton, Anna; Walsh, Steven; Tan, Tiong Kit; Schimanski, Lisa; Huang, Kuan-Ying A; Schuster, Catherine; Watashi, Koichi; Hinks, Timothy SC; Jagannath, Aarti; Vausdevan, Sridhar R; Bailey, Dalan; Baumert, Thomas F; McKeating, Jane A

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 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.