Role of Double-Stranded RNA Pattern Recognition Receptors in Rhinovirus-Induced Airway Epithelial Cell Responses

Rhinovirus (RV), a ssRNA virus of the picornavirus family, is a major cause of the common cold as well as asthma and chronic obstructive pulmonary disease exacerbations. Viral dsRNA produced during replication may be recognized by the host pattern recognition receptors TLR-3, retinoic acid-inducible...

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Published in:	The Journal of immunology (1950) Vol. 183; no. 11; pp. 6989 - 6997
Main Authors:	Wang, Qiong, Nagarkar, Deepti R, Bowman, Emily R, Schneider, Dina, Gosangi, Babina, Lei, Jing, Zhao, Ying, McHenry, Christina L, Burgens, Richai V, Miller, David J, Sajjan, Umadevi, Hershenson, Marc B
Format:	Journal Article
Language:	English
Published:	United States Am Assoc Immnol 01-12-2009
Subjects:	Blotting, Western Cell Line DEAD Box Protein 58 DEAD-box RNA Helicases - biosynthesis DEAD-box RNA Helicases - genetics DEAD-box RNA Helicases - immunology Epithelial Cells - immunology Epithelial Cells - virology Gene Expression Humans Interferon-Induced Helicase, IFIH1 Picornaviridae Infections - immunology Receptors, Immunologic Receptors, Pattern Recognition - biosynthesis Receptors, Pattern Recognition - genetics Receptors, Pattern Recognition - immunology Respiratory Mucosa - immunology Respiratory Mucosa - virology Reverse Transcriptase Polymerase Chain Reaction Rhinovirus - immunology RNA, Double-Stranded - immunology RNA, Small Interfering Signal Transduction - immunology Toll-Like Receptor 3 - biosynthesis Toll-Like Receptor 3 - genetics Toll-Like Receptor 3 - immunology
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Summary:	Rhinovirus (RV), a ssRNA virus of the picornavirus family, is a major cause of the common cold as well as asthma and chronic obstructive pulmonary disease exacerbations. Viral dsRNA produced during replication may be recognized by the host pattern recognition receptors TLR-3, retinoic acid-inducible gene (RIG)-I, and melanoma differentiation-associated gene (MDA)-5. No study has yet identified the receptor required for sensing RV dsRNA. To examine this, BEAS-2B human bronchial epithelial cells were infected with intact RV-1B or replication-deficient UV-irradiated virus, and IFN and IFN-stimulated gene expression was determined by quantitative PCR. The separate requirements of RIG-I, MDA5, and IFN response factor (IRF)-3 were determined using their respective small interfering RNAs (siRNA). The requirement of TLR3 was determined using siRNA against the TLR3 adaptor molecule Toll/IL-1R homologous region-domain-containing adapter-inducing IFN-beta (TRIF). Intact RV-1B, but not UV-irradiated RV, induced IRF3 phosphorylation and dimerization, as well as mRNA expression of IFN-beta, IFN-lambda1, IFN-lambda2/3, IRF7, RIG-I, MDA5, 10-kDa IFN-gamma-inducible protein/CXCL10, IL-8/CXCL8, and GM-CSF. siRNA against IRF3, MDA5, and TRIF, but not RIG-I, decreased RV-1B-induced expression of IFN-beta, IFN-lambda1, IFN-lambda2/3, IRF7, RIG-I, MDA5, and inflammatory protein-10/CXCL10 but had no effect on IL-8/CXCL8 and GM-CSF. siRNAs against MDA5 and TRIF also reduced IRF3 dimerization. Finally, in primary cells, transfection with MDA5 siRNA significantly reduced IFN expression, as it did in BEAS-2B cells. These results suggest that TLR3 and MDA5, but not RIG-I, are required for maximal sensing of RV dsRNA and that TLR3 and MDA5 signal through a common downstream signaling intermediate, IRF3.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.0901386