This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, Y. Articles by Brasier, A. R. Search for Related Content PubMed PubMed Citation Articles by Zhang, Y. Articles by Brasier, A. R.

 Previous Article  |  Next Article 

Journal of Virology, May 2003, p. 5933-5947, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5933-5947.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ribavirin Treatment Up-Regulates Antiviral Gene Expression via the Interferon-Stimulated Response Element in Respiratory Syncytial Virus-Infected Epithelial Cells

Departments of Medicine,¹ Pediatrics,² Microbiology and Immunology,³ Sealy Center for Molecular Sciences, The University of Texas Medical Branch, Galveston, Texas 77555-1060⁴

Received 18 November 2002/ Accepted 7 February 2003

Respiratory syncytial virus (RSV) is a mucosa-restricted virus that is a leading cause of epidemic respiratory tract infections in children. RSV replication is a potent activator of the epithelial-cell genomic response, influencing the expression of a spectrum of cellular pathways, including proinflammatory chemokines of the CC, CXC, and CX₃C subclasses. Ribavirin (1-ß-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nontoxic antiviral agent currently licensed for the treatment of severe RSV lower respiratory tract infections. Because ribavirin treatment reduces the cytopathic effect in infected cells, we used high-density microarrays to investigate the hypothesis that ribavirin modifies the virus-induced epithelial genomic response to replicating virus. Ribavirin treatment administered in concentrations of 10 to 100 µg/ml potently inhibited RSV transcription, thereby reducing the level of RSV N transcripts to 13% of levels in nontreated cells. We observed that in both the absence and the presence of ribavirin, RSV infection induced global alterations in the host epithelial cell, affecting 49% of the 6,650 expressed genes detectable by the microarray. Ribavirin influences the expression of only 7.5% of the RSV-inducible genes (total number of genes, 272), suggesting that the epithelial-cell genetic program initiated by viral infection is independent of high-level RSV replication. Hierarchical clustering of the ribavirin-regulated genes identified four expression patterns. In one group, ribavirin inhibited the expression of the RSV-inducible CC chemokines MIP-1 and -1ß, which are important in RSV-induced pulmonary pathology, and interferon (IFN), a cytokine important in the mucosal immune response. In a second group, ribavirin further up-regulated a set of RSV- and IFN-stimulated response genes (ISGs) encoding antiviral proteins (MxA and p56), complement products, acute-phase response factors, and the STAT and IRF transcription factors. Because IFN-ß expression itself was reduced in the ribavirin-treated cells, we further investigated the mechanism for up-regulation of the IFN-signaling pathway. Enhanced expression of IFI 6-16, IFI 9-27, MxA/p78, STAT-1, STAT-1ß, IRF-7B, and TAP-1-LMP2 transcripts were independently reproduced by Northern blot analysis. Ribavirin-enhanced TAP-1-LMP2 expression was a transcriptional event where site mutations of the IFN-stimulated response element (ISRE) blocked RSV and ribavirin-inducible promoter activity. Furthermore, ribavirin up-regulated the transcriptional activity of a reporter gene selectively driven by the ISRE. In specific DNA pull-down assays, we observed that ribavirin enhanced RSV-induced STAT-1 binding to the ISRE. We conclude that ribavirin potentiates virus-induced ISRE signaling to enhance the expression of antiviral ISGs, suggesting a mechanism for the efficacy of combined treatment with ribavirin and IFN in other chronic viral diseases.

This article has been cited by other articles:

• Dogra, N., Warburton, C., McMaster, W. R. (2007). Leishmania major Abrogates Gamma Interferon-Induced Gene Expression in Human Macrophages from a Global Perspective. Infect. Immun. 75: 3506-3515 [Abstract] [Full Text]  
• Janssen, R., Pennings, J., Hodemaekers, H., Buisman, A., van Oosten, M., de Rond, L., Ozturk, K., Dormans, J., Kimman, T., Hoebee, B. (2007). Host Transcription Profiles upon Primary Respiratory Syncytial Virus Infection. J. Virol. 81: 5958-5967 [Abstract] [Full Text]  
• Liu, P., Jamaluddin, M., Li, K., Garofalo, R. P., Casola, A., Brasier, A. R. (2007). Retinoic Acid-Inducible Gene I Mediates Early Antiviral Response and Toll-Like Receptor 3 Expression in Respiratory Syncytial Virus-Infected Airway Epithelial Cells. J. Virol. 81: 1401-1411 [Abstract] [Full Text]  
• McLaren, P. J., Mayne, M., Rosser, S., Moffatt, T., Becker, K. G., Plummer, F. A., Fowke, K. R. (2004). Antigen-Specific Gene Expression Profiles of Peripheral Blood Mononuclear Cells Do Not Reflect Those of T-Lymphocyte Subsets. CVI 11: 977-982 [Abstract] [Full Text]  
• Patel, N. J., Hansen, A., Merati, A. L., Kerschner, J. E. (2004). STAT3 Activation in Recurrent Respiratory Papillomatosis. Arch Otolaryngol Head Neck Surg 130: 1043-1045 [Abstract] [Full Text]  
• Bonville, C. A., Lau, V. K., DeLeon, J. M., Gao, J.-L., Easton, A. J., Rosenberg, H. F., Domachowske, J. B. (2004). Functional Antagonism of Chemokine Receptor CCR1 Reduces Mortality in Acute Pneumovirus Infection In Vivo. J. Virol. 78: 7984-7989 [Abstract] [Full Text]  
• Easton, A. J., Domachowske, J. B., Rosenberg, H. F. (2004). Animal Pneumoviruses: Molecular Genetics and Pathogenesis. Clin. Microbiol. Rev. 17: 390-412 [Abstract] [Full Text]  
• Rodriguez, L., Cuesta, I., Asenjo, A., Villanueva, N. (2004). Human respiratory syncytial virus matrix protein is an RNA-binding protein: binding properties, location and identity of the RNA contact residues. J. Gen. Virol. 85: 709-719 [Abstract] [Full Text]  
• Liu, T., Castro, S., Brasier, A. R., Jamaluddin, M., Garofalo, R. P., Casola, A. (2004). Reactive Oxygen Species Mediate Virus-induced STAT Activation: ROLE OF TYROSINE PHOSPHATASES. J. Biol. Chem. 279: 2461-2469 [Abstract] [Full Text]