- Title
- Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice
- Creator
- Kaiko, Gerard E.; Loh, Zhixuan; Diener, Kerrilyn R.; Baines, Katherine J.; Simpson, Jodie L.; Foster, Paul S.; Phipps, Simon; Spann, Kirsten; Lynch, Jason P.; Lalwani, Amit; Zheng, Zhenglong; Davidson, Sophia; Uematsu, Satoshi; Akira, Shizuo; Hayball, John
- Relation
- NHMRC
- Relation
- Journal of Allergy and Clinical Immunology Vol. 131, Issue 5, p. 1331-1339.e10
- Publisher Link
- http://dx.doi.org/10.1016/j.jaci.2013.02.041
- Publisher
- Mosby
- Resource Type
- journal article
- Date
- 2013
- Description
- 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/βlow, IL-12p70low, IL-1βhigh, IL-25high, and IL-33high 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. Conclusion: TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.
- Subject
- Toll-like receptor 7; Pneumovirus; infection; type 2 innate lymphoid cell; nuocyte; asthma; IL-13; exacerbation; respiratory syncytial virus; bronchiolitis
- Identifier
- http://hdl.handle.net/1959.13/1300520
- Identifier
- uon:20102
- Identifier
- ISSN:0091-6749
- Language
- eng
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