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

PLoS Pathogens

David J. Miller¹  Emily R. Bowman²  Dina Schneider³  Qiong Wang³  Umadevi S. Sajjan⁴  Deepti R. Nagarkar⁴  J. Kelley Bentley⁴  Ying Zhao⁴  Marisa J. Linn⁴  Adam M. Goldsmith⁴  Marc B. Hershenson⁴ 

[1] Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America;Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America;Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America;Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, United States of America

关键词: Respiratory infections;    Inflammation;    Mouse models;    Toll-like receptors;    Interferons;    Inflammatory diseases;    Immune receptor signaling;    Cytokines;   

DOI  :  10.1371/journal.ppat.1002070

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY