Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice - 29/04/13
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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-⍺/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.
Le texte complet de cet article est disponible en PDF.Key words : Toll-like receptor 7, Pneumovirus, infection, type 2 innate lymphoid cell, nuocyte, asthma, IL-13, exacerbation, respiratory syncytial virus, bronchiolitis
Abbreviations used : AEC, APC, BAL, cDC, DLN, dpi, ILC, LRT, pDC, PE, PFU, PRR, PVM, RSV, TLR7, TSLP
Plan
Supported by a National Health and Medical Research Council of Australia project grant (to S.P. and J.L.S.). |
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Disclosure of potential conflict of interest: G. E. Kaiko has received travel support from the Keystone Symposia. J. L. Simpson and S. Phipps have received grants from the National Health and Medical Research Council. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 5
P. 1331 - mai 2013 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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