title: Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice.
abstract: BACKGROUND
  Respiratory tract viruses are a major environmental risk factor for both the inception and exacerbations of asthma. Genetic defects in Toll-like receptor (TLR) 7-mediated signaling, impaired type I interferon responses, or both have been reported in asthmatic patients, although their contribution to the onset and exacerbation of asthma remains poorly understood.
  
  
  OBJECTIVE
  We sought to determine whether Pneumovirus infection in the absence of TLR7 predisposes to bronchiolitis and the inception of asthma.
  
  
  METHODS
  Wild-type and TLR7-deficient (TLR7(-/-)) mice were inoculated with the rodent-specific pathogen pneumonia virus of mice at 1 (primary), 7 (secondary), and 13 (tertiary) weeks of age, and pathologic features of bronchiolitis or asthma were assessed. In some experiments infected mice were exposed to low-dose cockroach antigen.
  
  
  RESULTS
  TLR7 deficiency increased viral load in the airway epithelium, which became sloughed and necrotic, and promoted an IFN-α/β(low), IL-12p70(low), IL-1β(high), IL-25(high), and IL-33(high) cytokine microenvironment that was associated with the recruitment of type 2 innate lymphoid cells/nuocytes and increased TH2-type cytokine production. Viral challenge of TLR7(-/-) mice induced all of the cardinal pathophysiologic features of asthma, including tissue eosinophilia, mast cell hyperplasia, IgE production, airway smooth muscle alterations, and airways hyperreactivity in a memory CD4(+) T cell-dependent manner. Importantly, infections with pneumonia virus of mice promoted allergic sensitization to inhaled cockroach antigen in the absence but not the presence of TLR7.
  
  
  CONCLUSIONS
  TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.
authors.affiliation: Centre for Asthma and Respiratory Diseases, University of Newcastle, Newcastle, Australia.
authors.forename: Gerard E
authors.initials: GE
authors.lastname: Kaiko
authors.forename: Zhixuan
authors.initials: Z
authors.lastname: Loh
authors.forename: Kirsten
authors.initials: K
authors.lastname: Spann
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lynch
authors.forename: Amit
authors.initials: A
authors.lastname: Lalwani
authors.forename: Zhenglong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Sophia
authors.initials: S
authors.lastname: Davidson
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: John
authors.initials: J
authors.lastname: Hayball
authors.forename: Kerrilyn R
authors.initials: KR
authors.lastname: Diener
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Baines
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Simpson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001249:Asthma / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D008168:Lung / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029122:Murine pneumonia virus / Q000472:pathogenicity; D018186:Pneumovirus Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000172:deficiency* / Q000235:genetics*; D019562:Viral Load
chemical_list: D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7