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

作者：Kaiko Gerard E; Loh Zhixuan; Spann Kirsten; Lynch Jason P; Lalwani Amit; Zheng Zhenglong; Davidson Sophia; Uematsu Satoshi; Akira Shizuo; Hayball John; Diener Kerrilyn R; Baines Katherine J; Simpson Jodie L; Foster Paul S; Phipps Simon^*

来源：Journal of Allergy and Clinical Immunology, 2013, 131(5): 1331-U132.

DOI：10.1016/j.jaci.2013.02.041

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

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. %26lt;br%26gt;Objective: We sought to determine whether Pneumovirus infection in the absence of TLR7 predisposes to bronchiolitis and the inception of asthma. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;Conclusion: TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.

• 出版日期2013-5