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 Keller, B. C. Articles by Gale, M. Search for Related Content PubMed PubMed Citation Articles by Keller, B. C. Articles by Gale, M., Jr.

Resistance to Alpha/Beta Interferon Is a Determinant of West Nile Virus Replication Fitness and Virulence

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9048,¹ Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110 ,² Texas Veterinary Medical Diagnostic Laboratory, Amarillo, Texas 79116-3200,³ Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0436⁴

Received 14 April 2006/ Accepted 18 July 2006

The emergence of West Nile virus (WNV) in the Western Hemisphere is marked by the spread of pathogenic lineage I strains, which differ from typically avirulent lineage II strains. To begin to understand the virus-host interactions that may influence the phenotypic properties of divergent lineage I and II viruses, we compared the genetic, pathogenic, and alpha/beta interferon (IFN-/ß)-regulatory properties of a lineage II isolate from Madagascar (MAD78) with those of a new lineage I isolate from Texas (TX02). Full genome sequence analysis revealed that MAD78 clustered, albeit distantly, with other lineage II strains, while TX02 clustered with emergent North American isolates, more specifically with other Texas strains. Compared to TX02, MAD78 replicated at low levels in cultured human cells, was highly sensitive to the antiviral actions of IFN in vitro, and demonstrated a completely avirulent phenotype in wild-type mice. In contrast to TX02 and other pathogenic forms of WNV, MAD78 was defective in its ability to disrupt IFN-induced JAK-STAT signaling, including the activation of Tyk2 and downstream phosphorylation and nuclear translocation of STAT1 and STAT2. However, replication of MAD78 was rescued in cells with a nonfunctional IFN-/ß receptor (IFNAR). Consistent with this finding, the virulence of MAD78 was unmasked upon infection of mice lacking IFNAR. Thus, control of the innate host response and IFN actions is a key feature of WNV pathogenesis and replication fitness.

This article has been cited by other articles:

• Davis, A. M., Hagan, K. A., Matthews, L. A., Bajwa, G., Gill, M. A., Gale, M. Jr., Farrar, J. D. (2008). Blockade of Virus Infection by Human CD4+ T Cells via a Cytokine Relay Network. J. Immunol. 180: 6923-6932 [Abstract] [Full Text]  
• Noueiry, A. O., Olivo, P. D., Slomczynska, U., Zhou, Y., Buscher, B., Geiss, B., Engle, M., Roth, R. M., Chung, K. M., Samuel, M., Diamond, M. S. (2007). Identification of Novel Small-Molecule Inhibitors of West Nile Virus Infection. J. Virol. 81: 11992-12004 [Abstract] [Full Text]  
• Scherbik, S. V., Stockman, B. M., Brinton, M. A. (2007). Differential Expression of Interferon (IFN) Regulatory Factors and IFN-Stimulated Genes at Early Times after West Nile Virus Infection of Mouse Embryo Fibroblasts. J. Virol. 81: 12005-12018 [Abstract] [Full Text]  
• Park, G. S., Morris, K. L., Hallett, R. G., Bloom, M. E., Best, S. M. (2007). Identification of Residues Critical for the Interferon Antagonist Function of Langat Virus NS5 Reveals a Role for the RNA-Dependent RNA Polymerase Domain. J. Virol. 81: 6936-6946 [Abstract] [Full Text]  
• Samuel, M. A., Diamond, M. S. (2006). Pathogenesis of West Nile Virus Infection: a Balance between Virulence, Innate and Adaptive Immunity, and Viral Evasion. J. Virol. 80: 9349-9360 [Full Text]