MDA5 and TLR3 Initiate Pro-Inflammatory Signaling Pathways Leading to Rhinovirus-Induced Airways Inflammation and Hyperresponsiveness

Abstract

Rhinovirus (RV), a single-stranded RNA picornavirus, is the most frequent cause of asthma exacerbations. We previously demonstrated in human bronchial epithelial cells that melanoma differentiation-associated gene (MDA)-5 and the adaptor protein for Toll-like receptor (TLR)-3 are each required for maximal RV1B-induced interferon (IFN) responses. However, in vivo, the overall airway response to viral infection likely represents a coordinated response integrating both antiviral and pro-inflammatory pathways. We examined the airway responses of MDA5- and TLR3-deficient mice to infection with RV1B, a minor group virus which replicates in mouse lungs. MDA5 null mice showed a delayed type I IFN and attenuated type III IFN response to RV1B infection, leading to a transient increase in viral titer. TLR3 null mice showed normal IFN responses and unchanged viral titers. Further, RV-infected MDA5 and TLR3 null mice showed reduced lung inflammatory responses and reduced airways responsiveness. Finally, RV-infected MDA5 null mice with allergic airways disease showed lower viral titers despite deficient IFN responses, and allergic MDA5 and TLR3 null mice each showed decreased RV-induced airway inflammatory and contractile responses. These results suggest that, in the context of RV infection, binding of viral dsRNA to MDA5 and TLR3 initiates pro-inflammatory signaling pathways leading to airways inflammation and hyperresponsiveness.

Differential Responses to Rhinovirus- and Influenza-associated Pulmonary Exacerbations in Patients with Cystic Fibrosis

“…We also found significant overexpression of the IFIH1 gene encoding MDA-5, an intracellular RNA helicase that recognizes viral doublestranded RNA. We have shown that, in contrast to RIG-I, MDA-5 expression is increased on RV infection in airway epithelial cells and is required for maximal RV-induced cytokine and IFN production in both human airway epithelial cells (43) and mouse lungs (44). Together, these data demonstrate that patients with CF with RV-associated respiratory exacerbations generate an antiviral response similar in character to that observed in experimental systems.…”

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

“…2010; Wang et al. 2011, 2009). While there is some controversy over whether or not NF‐ κ B p65 is required for RV‐induced IFN transcription (Bartlett et al.…”

MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells

“…TLR3 activation induces production of allergen-specific IgE and IgG1 (38). TLR3 null mice shows decreased rhinovirus-induced airway inflammatory and contractile responses (39). Poly(I:C) (TLR3) stimulation increases the secretion of IL-6 and GM-CSF from the nasal mucosa and the epithelial cell lines (40).…”