Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:131

Article

Kaiko, Gerard E.^1,2,3  Loh, Zhixuan⁴  Spann, Kirsten^5,6  Lynch, Jason P.⁴  Lalwani, Amit⁴  Zheng, Zhenglong⁴  Davidson, Sophia^1,2  Uematsu, Satoshi⁷  Akira, Shizuo⁷  Hayball, John⁸  Diener, Kerrilyn R.^8,9  Baines, Katherine J.^1,10  Simpson, Jodie L.^1,10  Foster, Paul S.^1,2,3  Phipps, Simon^4,6 

[1] Univ Newcastle, Ctr Asthma & Resp Dis, Callaghan, NSW 2308, Australia

[2] Univ Newcastle, Hunter Med Res Inst, Callaghan, NSW 2308, Australia

[3] Cooperat Res Ctr CRC Asthma & Airways, Sydney, NSW, Australia

[4] Univ Queensland, Sch Biomed Sci, S Lucia, Qld 4072, Australia

[5] Univ Queensland, Sir Albert Sakzewski Virus Res Ctr, S Lucia, Qld 4072, Australia

[6] Univ Queensland, Australian Infect Dis Res Ctr, S Lucia, Qld 4072, Australia

[7] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Host Def Lab, Suita, Osaka 565, Japan

[8] Univ S Australia, Sansom Inst, Expt Therapeut Lab, Adelaide, SA 5001, Australia

[9] Univ Adelaide, Robinson Inst, Adelaide, SA 5005, Australia

[10] John Hunter Hosp, Hunter Med Res Inst, Dept Resp & Sleep Med, Newcastle, NSW, Australia

关键词: Toll-like receptor 7;    Pneumovirus;    infection;    type 2 innate lymphoid cell;    nuocyte;    asthma;    IL-13;    exacerbation;    respiratory syncytial virus;    bronchiolitis;   

DOI  :  10.1016/j.jaci.2013.02.041

来源: Elsevier

【 摘 要 】

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-alpha/beta(low), IL-12p70(low), IL-1 beta(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 T(H)2-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.

【 授权许可】

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