Venezuelan equine encephalitis virus disrupts STAT1 signaling by distinct mechanisms independent of host shutoff.
ABSTRACT Venezuelan equine encephalitis virus (VEEV) is an important human and veterinary pathogen causing sporadic epizootic outbreaks of potentially fatal encephalitis. The type I interferon (IFN) system plays a central role in controlling VEEV and other alphavirus infections, and IFN evasion is likely an important determinant of whether these viruses disseminate and cause disease within their hosts. Alphaviruses are thought to limit the induction of type I IFNs and IFN-stimulated genes by shutting off host cell macromolecular synthesis, which in the case of VEEV is partially mediated by the viral capsid protein. However, more specific strategies by which alphaviruses inhibit type I IFN signaling have not been characterized. Analyses of cells infected with VEEV and VEEV replicon particles (VRP) demonstrate that viral infection rapidly disrupts tyrosine phosphorylation and nuclear translocation of the transcription factor STAT1 in response to both IFN-beta and IFN-gamma. This effect was independent of host shutoff and expression of viral capsid, suggesting that VEEV uses novel mechanisms to interfere with type I and type II IFN signaling. Furthermore, at times when STAT1 activation was efficiently inhibited, VRP infection did not limit tyrosine phosphorylation of Jak1, Tyk2, or STAT2 after IFN-beta treatment but did inhibit Jak1 and Jak2 activation in response to IFN-gamma, suggesting that VEEV interferes with STAT1 activation by the type I and II receptor complexes through distinct mechanisms. Identification of the viral requirements for this novel STAT1 inhibition will further our understanding of alphavirus molecular pathogenesis and may provide insights into effective alphavirus-based vaccine design.
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ABSTRACT: Extracellular proteins bound to cell-surface receptors can change nuclear gene expression patterns in minutes, with far-reaching consequences for development, cell growth and homeostasis. The signal transducer and activator of transcription (STAT) proteins are among the most well studied of the latent cytoplasmic signal-dependent transcription-factor pathways. In addition to several roles in normal cell decisions, dysregulation of STAT function contributes to human disease, making the study of these proteins an important topic of current research.Nature Reviews Molecular Cell Biology 10/2002; 3(9):651-62. · 39.12 Impact Factor
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ABSTRACT: The interface between an infectious agent and its host represents the ultimate battleground for survival: The microbe must secure a niche for replication, whereas the host must limit the pathogen's advance. Among the host's arsenal of antimicrobial factors, the type 1 interferons (IFNs) induce potent defense mechanisms against viruses and are key in the host-virus standoff. Viruses have evolved multiple tricks to avoid the immediate antiviral effects of IFNs and, in turn, hosts have adapted use of this innate cytokine system to galvanize multiple additional layers of immune defense. The plasticity that exists in these interactions provides us with a lesson in détente.Science 06/2006; 312(5775):879-82. · 31.20 Impact Factor
Article: In vitro synthesis of infectious venezuelan equine encephalitis virus RNA from a cDNA clone: analysis of a viable deletion mutant.[show abstract] [hide abstract]
ABSTRACT: A molecular clone of Venezuelan equine encephalitis virus (VEE) was constructed from four cDNAs that were synthesized using the viral RNA genome as template. Together, these cDNAs are believed to represent all but the nine 5'-terminal nucleotides of the VEE genome sequence. A T7 promoter, followed by a single intervening G residue, and the exact 5'-terminus of VEE were added to the 5'-most clone using in vitro mutagenesis. Appropriate restriction fragments isolated from the cloned cDNAs were joined to form a candidate full-length VEE cDNA clone. RNA transcripts synthesized in vitro from the cDNA clone were able to initiate a productive infection in DEAE-dextran-treated chicken embryo fibroblasts (CEF). VEE antigens were demonstrated in RNA-transfected cells, and supernatants from transfected cultures contained infectious virus particles. The candidate full-length cDNA clone lacked 102 nucleotides of the VEE genome sequence. The deletion, which also was present in the genomes of progeny virions derived from the clone, did not appear to affect growth in cultured CEF, baby hamster kidney cells, or Vero cells. The site of the deletion was mapped to the 3'-end of the nsP3 gene by comparison to other alphavirus sequences. In this region, the VEE genome sequence includes two tandem 102-nucleotide repeats which can be arranged in a stable stem and loop structure. The sequence remaining in the deleted clone retains one copy of the duplicated sequence and, in addition, faithfully preserves a portion of the predicted stem.Virology 08/1989; 171(1):189-204. · 3.35 Impact Factor