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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901386v1 183/11/6989    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Wang, Q. Articles by Hershenson, M. B. PubMed PubMed Citation Articles by Wang, Q. Articles by Hershenson, M. B.

Role of Double-Stranded RNA Pattern Recognition Receptors in Rhinovirus-Induced Airway Epithelial Cell Responses¹

Qiong Wang,^* Deepti R. Nagarkar,^* Emily R. Bowman, Dina Schneider, Babina Gosangi, Jing Lei, Ying Zhao, Christina L. McHenry, Richai V. Burgens, David J. Miller, Umadevi Sajjan, and Marc B. Hershenson^2*

^*Department of Molecular and Integrative Physiology, Department of Pediatrics and Communicable Diseases, and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109

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-β (TRIF). Intact RV-1B, but not UV-irradiated RV, induced IRF3 phosphorylation and dimerization, as well as mRNA expression of IFN-β, IFN-1, IFN-2/3, IRF7, RIG-I, MDA5, 10-kDa IFN--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-β, IFN-1, IFN-2/3, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL81420 and 82550 (to M.B.H.).

² Address correspondence and reprint requests to Dr. Marc B. Hershenson, University of Michigan, 1150 West Medical Center Drive, Room 3570, MSRBII, Box 5688, Ann Arbor, MI 48109-0688. E-mail address: mhershen{at}umich.edu

³ Abbreviations used in this paper: RV, rhinovirus; TRIF, TIR-domain-containing adapter-inducing IFN-β; RIG, retinoic acid-inducible gene; MDA, melanoma differentiation-associated gene; IKK, IB kinase; IRF, IFN response factor; IP-10, 10-kDa IFN--inducible protein; EMCV, encephalomyocarditis; DC, dendritic cell; BEGM, bronchial epithelial growth medium; ISG, IFN-stimulated gene; TIR, Toll/IL-1R homologous region; PRR, pattern recognition receptor; poly(IC), polyinosinic-polyadenylic acid.