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

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• 作者：Gerard E. Kaiko ; PhD ; BBiomedSc (Hons)^a ; ^b ; ^c ; Zhixuan Loh ; BSc (Hons)^d ; Kirsten Spann ; PhD ; BSc (Hons)^e ; ^f ; Jason P. Lynch ; BSc (Hons)^d ; Amit Lalwani ; BSc (Hons)^d ; Zhenglong Zheng ; BSc (Hons)^d ; Sophia Davidson ; BSc (Hons)^a ; ^b ; Satoshi Uematsu ; MD ; PhD^g ; Shizuo Akira ; MD ; PhD^g ; John Hayball ; PhD^h ; Kerrilyn R. Diener ; PhD^h ; ⁱ ; Katherine J. Baines ; PhD ; BBiomedSci (Hons)^a ; ^j ; Jodie L. Simpson ; PhD ; BSc (Hons)^a ; ^j ; Paul S. Foster ; PhD ; BSc (Hons)^a ; ^b ; ^c ; Simon Phipps ; PhD ; BSc (Hons)^d ; ^f ; ^{s.phipps@uq.edu.au}
• 关键词：Toll-like receptor 7 ; Pneumovirus ; infection ; type 2 innate lymphoid cell ; nuocyte ; asthma ; IL-13 ; exacerbation ; respiratory syncytial virus ; bronchiolitis
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：131
• 期：5
• 页码：1331-1339.e10
• 全文大小：1216 K

文摘

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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-¦Á/¦Â^low, IL-12p70^low, IL-1¦Â^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_H2-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.