title: Aeroallergen-induced IL-33 predisposes to respiratory virus-induced asthma by dampening antiviral immunity.
abstract: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized.
  
  
  
  We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections.
  
  
  
  Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release.
  
  
  
  PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-α and IFN-λ production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE-induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice. Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-α production.
  
  
  
  We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lynch
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Rhiannon B
authors.initials: RB
authors.lastname: Werder
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Simpson
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Zhixuan
authors.initials: Z
authors.lastname: Loh
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Vivian
authors.initials: V
authors.lastname: Zhang
authors.affiliation: QIMR Berghofer Medical Institute, Brisbane, Australia.
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.affiliation: School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Spann
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia; Centre for Children's Health Research, University of Queensland, Brisbane, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sly
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Mazzone
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia; Lung and Allergy Research Centre, School of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: John W
authors.initials: JW
authors.lastname: Upham
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Australia. Electronic address: s.phipps@uq.edu.au.
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
mesh_terms: D000393:Air Pollutants / Q000276:immunology; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000821:virology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology / Q000821:virology; D003058:Cockroaches; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D019476:Insect Proteins / Q000276:immunology*; D008168:Lung / Q000821:virology; D008807:Mice, Inbred BALB C; D029122:Murine pneumonia virus; D018186:Pneumovirus Infections / Q000276:immunology* / Q000821:virology; D019562:Viral Load
chemical_list: D000393:Air Pollutants; D000485:Allergens; D016207:Cytokines; D019476:Insect Proteins
keywords: IL-33; Pneumonia virus of mice; antiviral; interferon; plasmacytoid dendritic cell; respiratory syncytial virus; type 2 innate lymphoid cell