Cell autonomous regulation of herpes and influenza virus infection by the circadian clock
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Authors
Edgar, Rachel S
Stangherlin, Alessandra
Nagy, Andras
Nicoll, Michael P
Efstathiou, Stacey
O’Neill, John S
Reddy, Akhilesh
Publication Date
2016-08-15Journal Title
Proceedings of the National Academy of Sciences
ISSN
0027-8424
Publisher
National Academy of Sciences
Volume
113
Pages
10085-10090
Language
English
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Edgar, R. S., Stangherlin, A., Nagy, A., Nicoll, M. P., Efstathiou, S., O’Neill, J. S., & Reddy, A. (2016). Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. Proceedings of the National Academy of Sciences, 113 10085-10090. https://doi.org/10.1073/pnas.1601895113
Abstract
Viruses are intracellular pathogens that hijack host cell machinery and biosynthetic resources to replicate. Rather than being constant, host physiology is rhythmic and undergoes circadian (24 hour) oscillation in a variety of virus-relevant pathways. Whether these daily rhythms impact on viral replication is not known. Here we show that the time of day at which the host is infected regulates virus progression in live mice and in individual cells. Furthermore, we demonstrate that herpes and influenza A virus infections are enhanced when host circadian rhythms are abolished by disrupting the key clock gene Bmal1. Intracellular trafficking, biosynthetic processes, protein synthesis and chromatin assembly all contribute to circadian regulation of virus infection. Moreover, herpesviruses differentially target components of the molecular circadian clockwork Our work thus demonstrates that viruses exploit the clockwork for their own gain, and that the clock therefore represents a novel target for modulating viral replication that extends beyond a single family of these important pathogens.
Sponsorship
A.B.R. acknowledges funding from the Wellcome Trust (083643/Z/07/Z, 100333/Z/12/Z and 100574/Z/12/Z), the European Research Council (ERC Starting Grant No. 281348, MetaCLOCK), the EMBO Young Investigators Programme, the Lister Institute of Preventative Medicine and the Medical Research Council (MRC_MC_UU_12012/5). A.D.N acknowledges funding from the People Programme (Marie Curie Actions) of the European Union Seventh Framework Programme (FP7/2007-2013; REA grant agreement 627630). We thank L. Ansel-Bollepalli for assistance with animal breeding, I. Robinson for assistance with pilot animal experiments, A. Snijders and H. Flynn (Francis Crick Institute Proteomics Core) for help with proteomics work, Cambridge NIHR BRC Cell Phenotyping Hub for flow cytometry assistance, A. Miyawaki (RIKEN Brain Science Institute, Japan) for Fucci2 lentiviral vectors, and H. Coleman, J. May and M. Jain for helpful discussions. We thank Prof J. Bass (Northwestern University, USA) for Bmal-/- mouse embryonic fibroblasts used in preliminary experiments, and N. Heaton and P. Palese (Icahn School of Medicine at Mount Sinai, USA) for PB2::Gaussia luciferase IAV (PR8 PB2::GLUC).
Funder references
MRC (MC_UU_12012/5)
Wellcome Trust (083643/Z/07/Z)
Wellcome Trust (100333/Z/12/Z)
Wellcome Trust (100574/Z/12/Z)
European Research Council (281348)
European Commission (627630)
Identifiers
External DOI: https://doi.org/10.1073/pnas.1601895113
This record's URL: https://www.repository.cam.ac.uk/handle/1810/257262
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