@article{wilson_sessions_leon_scholle_2008, title={West Nile virus nonstructural protein 1 inhibits TLR3 signal transduction}, volume={82}, ISSN={["1098-5514"]}, DOI={10.1128/JVI.00226-08}, abstractNote={ABSTRACT
          The innate immune response is the first line of defense against foreign pathogens. The recognition of virus-associated molecular patterns, including double- and single-stranded RNA, by pattern recognition receptors initiates a cascade of signaling reactions. These result in the transcriptional upregulation and secretion of proinflammatory cytokines that induce an antiviral state. Many viruses have evolved mechanisms to antagonize these responses in order to help them establish a productive infection. We have previously shown that West Nile virus (WNV) is able to inhibit Toll-like receptor 3 (TLR3)-mediated activation of interferon (IFN) regulatory factor 3 (IRF3) (F. Scholle and P. W. Mason, Virology 342:77-87, 2005). In the present study, the WNV nonstructural (NS) proteins were analyzed individually for their ability to antagonize signal transduction mediated by TLR3. We report that expression of WNV NS1 inhibits TLR3-induced transcriptional activation of the IFN-β promoter and of an NF-κB-responsive promoter. This inhibition was due to a failure of the TLR3 ligand poly(I:C) to induce nuclear translocation of IRF3 and NF-κB. Furthermore, NS1 expression also inhibited TLR3-dependent production of interleukin-6 and the establishment of an antiviral state. The function of NS1 in flavivirus infection is not well understood. NS1 is required for viral RNA replication and is also secreted from mammalian cells but not from insect cells. Here, we identify a previously unrecognized role for NS1 in the modulation of signaling pathways of the innate immune response to WNV infection.}, number={17}, journal={JOURNAL OF VIROLOGY}, author={Wilson, Jason R. and Sessions, Paola Florez and Leon, Megan A. and Scholle, Frank}, year={2008}, month={Sep}, pages={8262–8271} }
 @article{bourne_scholle_silva_rossi_dewsbury_judy_de aguiar_leon_estes_fayzulin_et al._2007, title={Early production of type I interferon during West Nile virus infection: Role for lymphoid tissues in IRF3-independent interferon production}, volume={81}, DOI={10.1128/JVI.00316-07}, abstractNote={ABSTRACTInfection of cells with flaviviruses in vitro is reduced by pretreatment with small amounts of type I interferon (IFN-α/β). Similarly, pretreatment of animals with IFN and experiments using mice defective in IFN signaling have indicated a role for IFN in controlling flavivirus disease in vivo. These data, along with findings that flavivirus-infected cells block IFN signaling, suggest that flavivirus infection can trigger an IFN response. To investigate IFN gene induction by the very first cells infected during in vivo infection with the flavivirus West Nile virus (WNV), we infected mice with high-titer preparations of WNV virus-like particles (VLPs), which initiate viral genome replication in cells but fail to spread. These studies demonstrated a brisk production of IFN in vivo, with peak levels of over 1,000 units/ml detected in sera between 8 and 24 h after inoculation by either the intraperitoneal or footpad route. The IFN response was dependent on genome replication, and WNV genomes and WNV antigen-positive cells were readily detected in the popliteal lymph nodes (pLN) of VLP-inoculated mice. High levels of IFN mRNA transcripts and functional IFN were also produced in VLP-inoculated IFN regulatory factor 3 null (IRF3−/−) mice, indicating that IFN production was independent of the IRF3 pathways to IFN gene transcription, consistent with the IFN type produced (predominantly α).}, number={17}, journal={Journal of Virology}, author={Bourne, N. and Scholle, F. and Silva, M. C. and Rossi, S. L. and Dewsbury, N. and Judy, B. and De Aguiar, J. B. and Leon, M. A. and Estes, D. M. and Fayzulin, R. and et al.}, year={2007}, pages={9100–9108} }