title: 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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
authors.forename: Emily R
authors.initials: ER
authors.lastname: Bowman
authors.forename: Deepti R
authors.initials: DR
authors.lastname: Nagarkar
authors.forename: Dina
authors.initials: D
authors.lastname: Schneider
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marisa J
authors.initials: MJ
authors.lastname: Linn
authors.forename: Adam M
authors.initials: AM
authors.lastname: Goldsmith
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.forename: Umadevi S
authors.initials: US
authors.lastname: Sajjan
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology*; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology*; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D008171:Lung Diseases / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010850:Picornaviridae Infections / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D012330:RNA, Double-Stranded / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D012229:Rhinovirus / Q000302:isolation & purification / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000502:physiology*
chemical_list: D012330:RNA, Double-Stranded; D012367:RNA, Viral; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D007372:Interferons; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1