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Journal of Virology, July 2004, p. 7737-7747, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7737-7747.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Host Response to West Nile Virus Infection Limits Viral Spread through the Activation of the Interferon Regulatory Factor 3 Pathway

Brenda L. Fredericksen,1 Maria Smith,2 Michael G. Katze,2 Pei-Yong Shi,3 and Michael Gale Jr.1*

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,1 Department of Microbiology, University of Washington, Seattle, Washington 98195,2 Wadsworth Center, New York State Department of Health, New York, New York 122013

Received 20 January 2004/ Accepted 3 March 2004

Recent outbreaks of West Nile Virus (WNV) have been associated with an increase in morbidity and mortality in humans, birds, and many other species. We have initiated studies to define the molecular mechanisms by which a recent pathogenic isolate of WNV evades the host cell innate antiviral response. Biochemical and microarray analyses demonstrated that WNV induced the expression of beta interferon (IFN-ß) and several IFN-stimulated genes late in infection of cultured human cells. The late expression of these antiviral genes was due to the delayed activation of the transcription factor IFN regulatory factor 3 (IRF-3). Despite this host response, WNV was still able to replicate efficiently. The effect of the IRF-3 pathway on WNV replication was assessed by examining virus replication and spread in cultures of wild-type or IRF-3-null mouse embryo fibroblasts. The absence of IRF-3 was marked by a significant increase in plaque size and a sustained production of infectious particles. Although the activation of the IRF-3 pathway was not sufficient to block virus replication, our results suggest that IRF-3 target genes function to constrain WNV infection and limit cell-to-cell virus spread.

* Corresponding author. Mailing address: 5323 Harry Hines Blvd., Dallas, TX 75390-9048. Phone: (214) 648-5940. Fax: (214) 648-5905. E-mail: Michael.Gale{at}UTSouthwestern.edu.

Journal of Virology, July 2004, p. 7737-7747, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7737-7747.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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