Double But Not Single-Stranded RNA Exacerbates Allergen-Induced Airway Hyperresponsiveness and Airway Inflammation

Viral infections are one of the major causes of asthma exacerbations. However, the mechanism underlying virus-induced pathological changes in asthma has not been fully elucidated. It also remains unclear which viral components exacerbate asthma. In this study, we investigated the effects two major viral components, single stranded (ss) RNA and double stranded (ds) RNA, known ligands of Toll-like receptor (TLR) 7 and TLR3, respectively, in an experimental model of asthma. Wild-type C57BL/6 mice were sensitized to ovalbumin (OVA), and subsequent to OVA challenge, two synthesized nucleotides, R848 or poly I:C, which mimic the viral components ssRNA and dsRNA, respectively, were administered intratracheally. After administration of the viral components, AHR, bronchoalveolar lavage cell composition and type 2 cytokine production were determined. OVA-sensitized and -challenged mice developed AHR and airway inflammation with eosinophil infiltration in the lung. Administration ssRNA-R848, failed to alter the induced changes in AHR and airway inflammation. In contrast, administration of dsRNA-poly I:C, significantly enhanced the development of AHR with increased levels of type 2 cytokines (IL-4, IL-5, IL-13) as well as the pro-allergic epithelial cell-derived proteins TSLP, IL-25, and IL-33. The major viral component dsRNA, but not ssRNA, is capable of enhancing lung allergic inflammation, suggesting that the activation of TLR3 but not TLR7 is a critical contributor to virus-mediated asthma exacerbation.