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:
| J. Bacteriol. | Mol. Cell. Biol. | Microbiol. Mol. Biol. Rev. |
|---|
| Clin. Vaccine Immunol. | ALL ASM JOURNALS |
|---|