Repository logo

Cell autonomous regulation of herpes and influenza virus infection by the circadian clock.

Accepted version



Change log


Edgar, Rachel S 
Stangherlin, Alessandra 
Nagy, Andras D 
Nicoll, Michael P 
Efstathiou, Stacey 


Viruses are intracellular pathogens that hijack host cell machinery and resources to replicate. Rather than being constant, host physiology is rhythmic, undergoing circadian (∼24 h) oscillations in many virus-relevant pathways, but whether daily rhythms impact on viral replication is unknown. We find that the time of day of host infection regulates virus progression in live mice and 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 transcription factor 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 demonstrates that viruses exploit the clockwork for their own gain and that the clock represents a novel target for modulating viral replication that extends beyond any single family of these ubiquitous pathogens.



circadian, clock, herpes, influenza, virus, ARNTL Transcription Factors, Animals, Biological Transport, CLOCK Proteins, Cell Line, Chromatin Assembly and Disassembly, Circadian Clocks, Circadian Rhythm, Cricetinae, Epithelial Cells, Female, Gene Expression Regulation, Genes, Reporter, Herpes Simplex, Herpesviridae Infections, Herpesvirus 1, Human, Host-Pathogen Interactions, Influenza A Virus, H1N1 Subtype, Luciferases, Mice, Mice, Knockout, Orthomyxoviridae Infections, Rhadinovirus, Tumor Virus Infections, Virus Replication

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN


Volume Title



Proceedings of the National Academy of Sciences
Medical Research Council (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)
Medical Research Council (MC_PC_12012)
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).