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Published ahead of print on October 6, 2005, doi:10.1165/rcmb.2004-0417OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 192-203, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2004-0417OC

Rhinovirus Induces Airway Epithelial Gene Expression through Double-Stranded RNA and IFN-Dependent Pathways

Yin Chen, Edward Hamati, Pak-Kei Lee, Wai-Ming Lee, Shinichiro Wachi, David Schnurr, Shigeo Yagi, Gregory Dolganov, Homer Boushey, Pedro Avila and Reen Wu

University of California at Davis, Davis; California Department of Health Services, Richmond; University of California at San Francisco, San Francisco, California; and University of Wisconsin, Madison, Wisconsin

Correspondence and requests for reprints should be addressed to Yin Chen, Ph.D., Center for Comparative Respiratory Biology and Medicine, Genomic and Biomedical Sciences Facility, Suite 6510, University of California at Davis, One Shields Ave., Davis, CA 95616. E-mail: yinchen{at}ucdavis.edu

Rhinovirus (RV) infection is the major cause of common colds and of asthma exacerbations. Because the epithelial cell layer is the primary target of RV infection, we hypothesize that RV-induced airway disease is associated with the perturbation of airway epithelial gene expression. In this study, well differentiated primary human airway epithelial cells were infected with either RV16 (major group) or RV1B (minor group). Transcriptional gene profiles from RV-infected and mock-infected control cells were analyzed by Affymetrix Genechip, and changes of the gene expression were confirmed by real-time RT-PCR analysis. At 24 h after infection, 48 genes induced by both viruses were identified. Most of these genes are related to the IFN pathway, and have been documented to have antiviral functions. Indeed, a significant stimulation of IFN-beta secretion was detected after RV16 infection. Neutralizing antibody specific to IFN-beta and a specific inhibitor of the Janus kinase pathway both significantly blocked the induction of RV-inducible genes. Further studies demonstrated that 2-aminopurine, a specific inhibitor double-stranded RNA–dependent protein kinase, could block both IFN-beta production and RV-induced gene expression. Thus, IFN-beta–dependent pathway is a part of the double-stranded RNA–initiated pathway that is responsible for RV-induced gene expression. Consistent with its indispensable role in the induction of antiviral genes, deactivation of this signaling pathway significantly enhanced viral production. Because increase of viral yield is associated with the severity of RV-induced airway illness, the discovery of an epithelial antiviral signaling pathway in this study will contribute to our understanding of the pathogenesis of RV-induced colds and asthma exacerbations.

Key Words: airway epithelium • gene expression • rhinovirus • transcriptional profiling




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