title: Defining critical roles for NF-κB p65 and type I interferon in innate immunity to rhinovirus.
abstract: The importance of NF-κB activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF-κB p65 nuclear expression, NF-κB p65 DNA binding in lung tissue and NF-κB-regulated airway inflammation. In vitro inhibition of NF-κB reduced rhinovirus-induced pro-inflammatory cytokines but did not affect type I/III interferon induction. Rhinovirus-infected p65-deficient mice exhibited reduced neutrophilic inflammation, yet interferon induction, antiviral responses and virus loads were unaffected, indicating that NF-κB p65 is required for pro-inflammatory responses, but redundant in interferon induction by rhinoviruses in vivo. Conversely, IFNAR1(-/-) mice exhibited enhanced neutrophilic inflammation with impaired antiviral immunity and increased rhinovirus replication, demonstrating that interferon signalling was critical to antiviral immunity. We thus provide new mechanistic insights into rhinovirus infection and demonstrate the therapeutic potential of targeting NF-κB p65 (to suppress inflammation but preserve anti-viral immunity) and type I IFN signalling (to enhance deficient anti-viral immunity) to treat rhinovirus-induced exacerbations of airway diseases.
authors.affiliation: Department of Respiratory Medicine, National Heart Lung Institute, Imperial College London, London, UK.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Bartlett
authors.forename: Louise
authors.initials: L
authors.lastname: Slater
authors.forename: Nicholas
authors.initials: N
authors.lastname: Glanville
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Haas
authors.forename: Gaetano
authors.initials: G
authors.lastname: Caramori
authors.forename: Paolo
authors.initials: P
authors.lastname: Casolari
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Clarke
authors.forename: Simon D
authors.initials: SD
authors.lastname: Message
authors.forename: Julia
authors.initials: J
authors.lastname: Aniscenko
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kebadze
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Patrick
authors.initials: P
authors.lastname: Mallia
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
authors.forename: Maria
authors.initials: M
authors.lastname: Belvisi
authors.forename: Alberto
authors.initials: A
authors.lastname: Papi
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kotenko
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
authors.forename: Michael R
authors.initials: MR
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D012229:Rhinovirus / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; D007370:Interferon Type I; D008840:Microfilament Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; C066559:Lcp1 protein, mouse; D053633:Receptor, Interferon alpha-beta