Summary The coronavirus disease 2019 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (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 to angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organism’s response to its environment and can regulate host susceptibility to virus infection. We demonstrate that silencing the circadian regulator Bmal1 or treating lung epithelial cells with the REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and replication. Importantly, treating infected cells with SR9009 limits SARS-CoV-2 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 interferon-stimulated gene transcripts in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to limit SARS-CoV-2 infection. Our study highlights alternative approaches to understand and improve therapeutic targeting of SARS-CoV-2. Graphical abstract Highlights • BMAL1 regulates ACE2-dependent SARS-CoV-2 entry • REV-ERB agonist reduces ACE2-dependent cell-cell fusion • Genetic or pharmacological targeting of BMAL1 reduces SARS-CoV-2 replication • BMAL1 regulates interferon-stimulated gene expression Molecular biology; Microbiology; Virology; Transcriptomics
【저자키워드】 Microbiology, Virology, Molecular biology, transcriptomics, 【초록키워드】 coronavirus disease, public health, SARS-CoV-2, ACE2, coronavirus, pandemic, SARS-COV-2 infection, spike glycoprotein, Replication, Health, pathway, respiratory tract, virus infection, cell-cell fusion, ACE2 expression, expression, transcriptome analysis, SARS-CoV-2 replication, Calu-3, mechanism, Lung epithelial cells, binding, Angiotensin-converting enzyme, regulate, host susceptibility, circadian rhythm, therapeutic targeting, acute respiratory syndrome, Particles, Abstract, SARS-CoV-2 entry, secretion, organism, viral life cycle, infected cell, Bmal1, interferon-stimulated gene, pharmacological, infect, transcript, limit, Cell, highlight, IMPROVE, caused, approach, inhibit, reduce, lung epithelial cell, 【제목키워드】 Replication, regulate, SARS-CoV-2 entry, Bmal1, circadian clock, lung epithelial cell,