Insights into Virus-Host Interactions: Regulation of Cytokine Signaling Is a Virulence Determinant of West Nile Virus

West Nile virus (WNV) has rapidly become a pathogen of global importance over the past two decades. Its recent association with severe neurological disease and emergence in the Western Hemisphere suggest that the virus has acquired the ability to effectively evade host immune defenses. One of the earliest steps in controlling viral infection occurs through the action of interferon (IFN) and its downstream activation of an antiviral state within the infected cell and neighboring tissue. To begin to understand how WNV evades host defenses, studies were initiated to examine the interaction of virulent (TX02) and avirulent (MAD78) WNV strains with the host IFN system. Compared to TX02, MAD78 replicated at lower 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. However, replication of MAD78 was rescued in cells lacking a functional IFNalpha /beta receptor (IFNAR). Consistent with this, MAD78 virulence was unmasked upon infection of mice lacking IFNAR. The regulation of IFN signaling was multifactorial involving a combination of viral and host factors. In particular, overexpression of various proteins from the pathogenic TX02 strain and the nonpathogenic MAD78 strain attenuated signaling to an IFN-responsive promoter, suggesting that viral products from both strains are capable of contributing to the IFN signal block. Differences between TX02 and MAD78 were identified, however, when host suppressors of cytokine signaling (SOCS) proteins were shown to be differentially upregulated by the two strains. Furthermore, expression of a dominant-negative form of SOCS1 partially restored IFN signaling during TX02 infection indicating that SOCS proteins do in fact participate in virus-induced signaling suppression. Importantly, WNV regulation of signaling was not restricted to IFNalpha /beta but included IFNgamma and IL-6, cytokines that similarly utilize JAK-STAT. These studies demonstrate novel insights into the complex interactions that occur between a virus and its infected host cell and may allow for the identification of viral and cellular targets for the development of improved therapeutics and new vaccine strategies.