title: BMAL1 links the circadian clock to viral airway pathology and asthma phenotypes.
abstract: Patients with asthma experience circadian variations in their symptoms. However it remains unclear how specific aspects of this common airway disease relate to clock genes, which are critical to the generation of circadian rhythms in mammals. Here, we used a viral model of acute and chronic airway disease to examine how circadian clock disruption affects asthmatic lung phenotypes. Deletion of the core clock gene bmal1 or environmental disruption of circadian function by jet lag exacerbated acute viral bronchiolitis caused by Sendai virus (SeV) and influenza A virus in mice. Post-natal deletion of bmal1 was sufficient to trigger increased SeV susceptibility and correlated with impaired control of viral replication. Importantly, bmal1-/-mice developed much more extensive asthma-like airway changes post infection, including mucus production and increased airway resistance. In human airway samples from two asthma cohorts, we observed altered expression patterns of multiple clock genes. Our results suggest a role for bmal1 in the development of asthmatic airway disease via the regulation of lung antiviral responses to common viral triggers of asthma.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ehlers
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.|Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.
authors.forename: W
authors.initials: W
authors.lastname: Xie
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: E
authors.initials: E
authors.lastname: Agapov
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: S
authors.initials: S
authors.lastname: Brown
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: D
authors.initials: D
authors.lastname: Steinberg
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Tidwell
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sajol
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Schutz
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Weaver
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Castro
authors.affiliation: Division of Pediatric Allergy, Immunology and Pulmonary Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Bacharier
authors.affiliation: Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Holtzman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Haspel
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics* / Q000378:metabolism; D056151:Airway Remodeling / Q000235:genetics; D000403:Airway Resistance / Q000235:genetics; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001990:Bronchiolitis, Viral / Q000276:immunology*; D057906:Circadian Clocks / Q000235:genetics*; D015331:Cohort Studies; D004195:Disease Models, Animal; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D010253:Respirovirus Infections / Q000276:immunology*; D029082:Sendai virus / Q000276:immunology*; D014779:Virus Replication
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse