期刊
ISCIENCE
卷 24, 期 10, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2021.103144
关键词
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资金
- Wellcome [200838/Z/16/Z, 104553/z/14/z, 211050/Z/18/z]
- UK Medical Research Council (MRC) [MR/R022011/1]
- Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China [2018-I2M-2-002]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [SCHI 1487/2-1]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Center
- BBSRC-UKRI [BB/N01992X/1]
- FRM
- ANR TargEnt-COVID-19
- Inserm
- University of Strasbourg
- Institut Universitaire de France
- Agence Nationale de Recherche sur le Sida et les hepatites virales (ANRS)
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [U19AI12386]
- ERC AdG HEPCIR
- European Union's Horizon 2020 research and innovation program [671231]
- FONDATION ARC TheraHCC2.0
- Fondation ARC pour la recherche sur le cancer [IHU201901299]
- BBSRC [BB/N01992X/1] Funding Source: UKRI
- Wellcome Trust [104553/Z/14/Z, 211050/Z/18/Z] Funding Source: Wellcome Trust
The study reveals that the circadian clock can impact SARS-CoV-2 infection, as silencing Bmal1 or treating lung epithelial cells with SR9009 can reduce viral replication. This finding suggests alternative approaches for understanding and improving therapeutic targeting of the virus.
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 limitsSARS-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.
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