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

• DOI: 10.1016/j.isci.2021.103144
• Publication Date: 2021-09-16T06:59:19Z
• Authors: 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. Huang; Catherine Schuster; Koichi Watashi; Timothy S.C. Hinks; Aarti Jagannath; Sridhar R. Vausdevan; Dalan Bailey; Thomas F. Baumert; Jane A. McKeating
• Keywords: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology; Molecular biology; Virology; Science; Q; Transcriptomics; Microbiology; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology; Article; 3. Good health

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.