MDA5 and TLR3 initiate pro-inflammatory signaling pathways leading to rhinovirus-induced airways inflammation and hyperresponsiveness

PLoS Pathog. 2011 May;7(5):e1002070. doi: 10.1371/journal.ppat.1002070. Epub 2011 May 26.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bronchial Hyperreactivity / metabolism
  • Bronchial Hyperreactivity / physiopathology*
  • Bronchial Hyperreactivity / virology*
  • DEAD-box RNA Helicases / physiology*
  • Disease Models, Animal
  • Inflammation / metabolism
  • Inflammation / physiopathology*
  • Inflammation / virology*
  • Interferon-Induced Helicase, IFIH1
  • Interferons / metabolism
  • Lung / metabolism
  • Lung / physiopathology
  • Lung / virology
  • Lung Diseases / metabolism
  • Lung Diseases / physiopathology
  • Lung Diseases / virology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Picornaviridae Infections / metabolism
  • Picornaviridae Infections / physiopathology
  • Picornaviridae Infections / virology
  • RNA, Double-Stranded / metabolism
  • RNA, Viral / metabolism
  • Rhinovirus / isolation & purification
  • Rhinovirus / physiology*
  • Signal Transduction / physiology*
  • Toll-Like Receptor 3 / physiology*


  • RNA, Double-Stranded
  • RNA, Viral
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Interferons
  • Ifih1 protein, mouse
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1