West Nile Virus Inhibits the Signal Transduction Pathway of Alpha Interferon

Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111, USA.
Journal of Virology (Impact Factor: 4.44). 03/2005; 79(3):1343-50. DOI: 10.1128/JVI.79.3.1343-1350.2005
Source: PubMed

ABSTRACT West Nile virus (WNV) is a human pathogen that can cause neurological disorders, including meningoencephalitis. Experiments with mice and mammalian cell cultures revealed that WNV exhibited resistance to the innate immune program induced by alpha interferon (IFN-alpha). We have investigated the nature of this inhibition and have found that WNV replication inhibited the activation of many known IFN-inducible genes, because it prevented the phosphorylation and activation of the Janus kinases JAK1 and Tyk2. As a consequence, activation of the transcription factors STAT1 and STAT2 did not occur in WNV-infected cells. Moreover, we demonstrated that the viral nonstructural proteins are responsible for this effect. Thus, our results provided an explanation for the observed resistance of WNV to IFN-alpha in cells of vertebrate origin.

Download full-text


Available from: Christoph Seeger, Sep 25, 2015
12 Reads
  • Source
    • "The structural proteins are components of virus particles, and play essential roles in viral entry, fusion and assembly. Nonstructural proteins are responsible for viral RNA replication (Lindenbach et al., 2007), evasion of innate immune response (Guo et al., 2005), and virus assembly (Kummerer and Rice, 2002; Xie et al., 2013). Among the ten viral proteins, only NS3 and NS5 have known enzymatic activities. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dengue virus (DENV) non-structural protein 4B (NS4B) has been demonstrated to be an attractive antiviral target. Due to its nature as an integral membrane protein, NS4B remains poorly characterized. In this study, we generated and characterized two monoclonal antibodies (mAb) that selectively bind to DENV NS4B protein. One mAb, 10-3-7, is specific for DENV-2 NS4B, and its epitope was mapped to residues 5–15 of NS4B. The other mAb, 44-4-7, cross-reacts with all the four serotypes of DENV NS4B, and its epitope was mapped to residues 141–147 of NS4B. Using the mAbs, we probed the intracellular orientation of the epitopes of NS4B by an epitope accessibility assay. The results showed that the N-terminus of NS4B is located in the ER lumen, whereas amino acids 130–148 of NS4B are located in the cytosol. The study demonstrates that the two anti-NS4B mAbs will be useful for future structural and functional analyses of DENV NS4B.
    Virology 02/2014; s 450–451:250–257. DOI:10.1016/j.virol.2013.12.025 · 3.32 Impact Factor
  • Source
    • "In the present study, a significant augmentation of STAT1 and STAT2 protein levels was detected at the early time-point and was maintained at the late time-point. The augmentation of STATs proteins could correspond to a host response following WNV infection, in agreement with previous findings [80], [81]. However, the increase of STAT protein abundance was not correlated with an increase of STAT phosphorylation states, as confirmed by WB using a p-701-STAT-1-specific antibody. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The recent West Nile virus (WNV) outbreaks in developed countries, including Europe and the United States, have been associated with significantly higher neuropathology incidence and mortality rate than previously documented. The changing epidemiology, the constant risk of (re-)emergence of more virulent WNV strains, and the lack of effective human antiviral therapy or vaccines makes understanding the pathogenesis of severe disease a priority. Thus, to gain insight into the pathophysiological processes in severe WNV infection, a kinetic analysis of protein expression profiles in the brain of WNV-infected mice was conducted using samples prior to and after the onset of clinical symptoms. To this end, 2D-DIGE and gel-free iTRAQ labeling approaches were combined, followed by protein identification by mass spectrometry. Using these quantitative proteomic approaches, a set of 148 proteins with modified abundance was identified. The bioinformatics analysis (Ingenuity Pathway Analysis) of each protein dataset originating from the different time-point comparisons revealed that four major functions were altered during the course of WNV-infection in mouse brain tissue: i) modification of cytoskeleton maintenance associated with virus circulation; ii) deregulation of the protein ubiquitination pathway; iii) modulation of the inflammatory response; and iv) alteration of neurological development and neuronal cell death. The differential regulation of selected host protein candidates as being representative of these biological processes were validated by western blotting using an original fluorescence-based method. This study provides novel insights into the in vivo kinetic host reactions against WNV infection and the pathophysiologic processes involved, according to clinical symptoms. This work offers useful clues for anti-viral research and further evaluation of early biomarkers for the diagnosis and prevention of severe neurological disease caused by WNV.
    PLoS ONE 12/2013; 8(7):e68318. DOI:10.1371/journal.pone.0068318 · 3.23 Impact Factor
  • Source
    • "We therefore looked for another mechanism, apart from STAT binding, that could mediate an effective blockade of type I IFN action. Studies with several other RNA viruses, such as Sendai virus [50], Marbug virus [35], Japanese encephalitis virus [51], [52], Langat virus [53], Dengue virus [54] and West Nile virus [55] have shown interference with the phosphorylation of receptor associated Janus kinases. We found that the virulent strain of RPV (RPV-Sa) had the ability to block type I IFN signalling at this early step in the pathway, blocking the phosphorylation of IFN receptor-associated kinases Jak1 and Tyk2. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Morbilliviruses form a closely related group of pathogenic viruses which encode three non-structural proteins V, W and C in their P gene. Previous studies with rinderpest virus (RPV) and measles virus (MeV) have demonstrated that these non-structural proteins play a crucial role in blocking type I (IFNα/β) and type II (IFNγ) interferon action, and various mechanisms have been proposed for these effects. We have directly compared four important morbilliviruses, rinderpest (RPV), measles virus (MeV), peste des petits ruminants virus (PPRV) and canine distemper virus (CDV). These viruses and their V proteins could all block type I IFN action. However, the viruses and their V proteins had varying abilities to block type II IFN action. The ability to block type II IFN-induced gene transcription correlated with co-precipitation of STAT1 with the respective V protein, but there was no correlation between co-precipitation of either STAT1 or STAT2 and the abilities of the V proteins to block type I IFN-induced gene transcription or the creation of the antiviral state. Further study revealed that the V proteins of RPV, MeV, PPRV and CDV could all interfere with phosphorylation of the interferon-receptor-associated kinase Tyk2, and the V protein of highly virulent RPV could also block the phosphorylation of another such kinase, Jak1. Co-precipitation studies showed that morbillivirus V proteins all form a complex containing Tyk2 and Jak1. This study highlights the ability of morbillivirus V proteins to target multiple components of the IFN signalling pathways to control both type I and type II IFN action.
    PLoS ONE 02/2013; 8(2):e57063. DOI:10.1371/journal.pone.0057063 · 3.23 Impact Factor
Show more