Article

Vaccinia virus blocks Stat1-dependent and Stat1-independent gene expression induced by type I and type II interferons.

Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research (impact factor: 1.63). 07/2008; 28(6):367-80. DOI:10.1089/jir.2007.0113
Source: PubMed

ABSTRACT Blocking the function of Stat (signal transducer and activator of transcription) proteins, which are critical for antiviral responses, has evolved as a common mechanism for pathogen immune evasion. The poxvirus-encoded phosphatase H1 is critical for viral replication, and may play an additional role in the evasion of host defense by dephosphorylating Stat1 and blocking interferon (IFN)-stimulated innate immune responses. Vaccinia virus (VACV) H1 can inhibit the phosphorylation of the transcription factor Stat1 after IFN-gamma stimulation of epithelial cells, greatly attenuating IFN-induced biological functions. In this study, we demonstrate that VACV infection is capable of inhibiting the phosphorylation of Stat1 and Stat2 after stimulation of fibroblasts or bone marrow-derived macrophages with either type I or type II IFNs, but did not inhibit the activation of Stat3 or Stat5 in either cell type. By using recombinant proteins for in vitro assays, we observe that variola virus H1 is more active than VACV H1, although it has similar selectivity for Stat targets. Differential effects of VACV infection were observed on the induction of IFN-stimulated genes, with complete inhibition of some genes by VACV infection, while others were less affected. Despite the IFN-gamma-induced expression of some genes in VACV-infected cells, IFN-gamma was unable to rescue the VACV-mediated inhibition of MHC class II antigen presentation. Moreover, VACV infection can affect the IFN-induced expression of Stat1-dependent and Stat1-independent genes, suggesting that the virus may target additional IFN-activated pathways. Thus, VACV targets multiple signaling pathways in the evasion of antiviral immune responses.

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Keywords

antiviral immune responses
 
attenuating IFN-induced biological functions
 
bone marrow-derived macrophages
 
cell type
 
dephosphorylating Stat1
 
IFN-gamma-induced expression
 
IFN-stimulated genes
 
MHC class II antigen presentation
 
pathogen immune evasion
 
poxvirus-encoded phosphatase H1
 
signal transducer
 
Stat1-independent genes
 
transcription factor Stat1
 
type II IFNs
 
Vaccinia virus
 
VACV H1
 
VACV targets multiple signaling pathways
 
variola virus H1
 
viral replication
 
vitro assays