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

• Published in: Journal of allergy and clinical immunology 2013-05, Vol.131 (5), p.1331-1339.e10
• Main Authors: Kaiko, Gerard E., PhD, BBiomedSc (Hons), Loh, Zhixuan, BSc (Hons), Spann, Kirsten, PhD, BSc (Hons), Lynch, Jason P., BSc (Hons), Lalwani, Amit, BSc (Hons), Zheng, Zhenglong, BSc (Hons), Davidson, Sophia, BSc (Hons), Uematsu, Satoshi, MD, PhD, Akira, Shizuo, MD, PhD, Hayball, John, PhD, Diener, Kerrilyn R., PhD, Baines, Katherine J., PhD, BBiomedSci (Hons), Simpson, Jodie L., PhD, BSc (Hons), Foster, Paul S., PhD, BSc (Hons), Phipps, Simon, PhD, BSc (Hons)
• Format: Article
• Language: English
• Subjects: Age; Allergy and Immunology; Animals; Animals, Newborn; asthma; Asthma - etiology; Asthma - immunology; Asthma - pathology; Biological and medical sciences; bronchiolitis; Chronic obstructive pulmonary disease, asthma; Disease Models, Animal; exacerbation; Fundamental and applied biological sciences. Psychology; Fundamental immunology; IL-13; Immunopathology; infection; Lung - pathology; Lung - physiopathology; Lung - virology; Medical sciences; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Murine pneumonia virus - pathogenicity; nuocyte; Pneumology; Pneumonia virus of mice; Pneumovirus; Pneumovirus Infections - complications; Pneumovirus Infections - immunology; Pneumovirus Infections - pathology; respiratory syncytial virus; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Toll-like receptor 7; Toll-Like Receptor 7 - deficiency; Toll-Like Receptor 7 - genetics; type 2 innate lymphoid cell; Viral Load
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.02.041

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 TH 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.