title: Cell autonomous regulation of herpes and influenza virus infection by the circadian clock.
abstract: 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.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Edgar
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Alessandra
authors.initials: A
authors.lastname: Stangherlin
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; Department of Anatomy, University of Pecs Medical School, H-7624 Pecs, Hungary;
authors.forename: Andras D
authors.initials: AD
authors.lastname: Nagy
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Nicoll
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Stacey
authors.initials: S
authors.lastname: Efstathiou
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom;
authors.forename: John S
authors.initials: JS
authors.lastname: O'Neill
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; areddy@cantab.net.
authors.forename: Akhilesh B
authors.initials: AB
authors.lastname: Reddy
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001692:Biological Transport; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D006224:Cricetinae; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006561:Herpes Simplex / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D006566:Herpesviridae Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000472:pathogenicity / Q000502:physiology; D054884:Host-Pathogen Interactions; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity / Q000502:physiology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D018144:Rhadinovirus / Q000472:pathogenicity / Q000502:physiology; D014412:Tumor Virus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D014779:Virus Replication
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D008156:Luciferases; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: circadian; clock; herpes; influenza; virus