title: Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia.
abstract: BACKGROUND
  Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), which is sensed by Toll-like receptors (TLR) such as TLR7. Some asthmatics have impaired interferon (IFN) responses to RV, but the underlying mechanisms of this clinically relevant observation are poorly understood.
  
  
  OBJECTIVE
  To investigate the importance of intact TLR7 signalling in vivo during RV exacerbation using mouse models of house dust mite (HDM)-induced allergic airways disease exacerbated by a superimposed RV infection.
  
  
  METHODS
  Wild-type and TLR7-deficient (Tlr7(-/-)) BALB/c mice were intranasally sensitised and challenged with HDM prior to infection with RV1B. In some experiments, mice were administered recombinant IFN or adoptively transferred with plasmacytoid dendritic cells (pDC).
  
  
  RESULTS
  Allergic Tlr7(-/-) mice displayed impaired IFN release upon RV1B infection, increased virus replication and exaggerated eosinophilic inflammation and airways hyper reactivity. Treatment with exogenous IFN or adoptive transfer of TLR7-competent pDCs blocked these exaggerated inflammatory responses and boosted IFNγ release in the absence of host TLR7 signalling. TLR7 expression in the lungs was suppressed by allergic inflammation and by interleukin (IL)-5-induced eosinophilia in the absence of allergy. Subjects with moderate-to-severe asthma and eosinophilic but not neutrophilic airways inflammation, despite inhaled steroids, showed reduced TLR7 and IFNλ2/3 expression in endobronchial biopsies. Furthermore, TLR7 expression inversely correlated with percentage of sputum eosinophils.
  
  
  CONCLUSIONS
  This implicates IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression and antiviral responses, which provides a molecular mechanism underpinning the effect of eosinophil-targeting treatments for the prevention of asthma exacerbations.
authors.affiliation: Department of Experimental & Translational Respiratory Medicine, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Hatchwell
authors.affiliation: Department of Experimental & Translational Respiratory Medicine, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Collison
authors.affiliation: Department of Experimental & Translational Respiratory Medicine, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Jason
authors.identifier: http://orcid.org/0000-0002-0739-1070
authors.initials: J
authors.lastname: Girkin
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.
authors.forename: Kristy
authors.initials: K
authors.lastname: Parsons
authors.affiliation: Department of Experimental & Translational Respiratory Medicine, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Norman Bethune Medical Science Centre, Jilin University, Jilin, Changchun, China.
authors.forename: Junyao
authors.initials: J
authors.lastname: Li
authors.affiliation: Norman Bethune Medical Science Centre, Jilin University, Jilin, Changchun, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The School of Biomedical Sciences, University of Queensland, Queensland, Queensland, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Darryl
authors.initials: D
authors.lastname: Knight
authors.affiliation: Airway Disease Infection Section, National Heart and Lung Institute, Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, Norfolk Place, London, UK.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Bartlett
authors.affiliation: Airway Disease Infection Section, National Heart and Lung Institute, Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, Norfolk Place, London, UK.
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.
authors.forename: Peter A B
authors.initials: PA
authors.lastname: Wark
authors.affiliation: Department of Experimental & Translational Respiratory Medicine, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia Department of Paediatric Respiratory and Sleep Medicine, Newcastle Children's Hospital, Newcastle, New South Wales, Australia.
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
mesh_terms: D000818:Animals; D004804:Eosinophils; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007372:Interferons / Q000378:metabolism*; D015848:Interleukin-5 / Q000378:metabolism*; D008168:Lung / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010850:Picornaviridae Infections / Q000378:metabolism / Q000473:pathology*; D011657:Pulmonary Eosinophilia / Q000378:metabolism / Q000473:pathology*; D039981:Pyroglyphidae; D060888:Real-Time Polymerase Chain Reaction; D012229:Rhinovirus / Q000302:isolation & purification*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D015848:Interleukin-5; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D007372:Interferons
keywords: Asthma; Innate Immunity; Pulmonary eosinophilia; Respiratory Infection