Vaccinia Virus Blocks Stat1-Dependent and Stat1-Independent Gene Expression Induced by Type I and Type II Interferons

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-γ 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 marrowderived 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-γ-induced expression of some genes in VACV-infected cells, IFN-γ 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.

A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus

“…Poxviruses, like most viruses, encode proteins that antagonize antiviral mechanisms mediated by IFN (reviewed in reference 25). VACV, an orthopoxvirus closely related to MPXV, encodes an inhibitor (H1) of phosphorylation of STAT1 and STAT2 following type 1 or type 2 IFN stimulation in vitro (23,31). VACV encodes IFN-binding proteins (B19 and B8) that block selected type 1 and 2 IFN-mediated induction of both STAT1-dependent and -independent genes and are both essential for virulence (7,28,32,48,57,61).…”

Poxvirus Proteomics and Virus-Host Protein Interactions

“…Based on the crystal structure, in silico screening was performed, and several novel compounds with potential antiviral properties were identified (126). Moreover, the phosphatase encoded by VACV (VH1) has been shown to dephosphorylate STAT1, resulting in the downregulation of the cellular antiviral response (99). This viral phosphatase is inactive against STAT1 bound to DNA, suggesting that the viral protein acts predominantly on activated STAT1 in the cytoplasm, which is relevant in light of the fact that the site of viral replication occurs in the cytoplasm for poxviruses.…”

Primary Human Macrophages Serve as Vehicles for Vaccinia Virus Replication and Dissemination

“…In different cell types, many of the IL-10 effects are mediated via the activation of the Jak2/Stat3 pathway, with Stat3 being a crucial factor for alternative activation in macrophages and immune homeostasis. VACV infection does not block Stat3 activity but does dephosphorylate Stat1 to reduce the effect of IFN stimulation (78). In general, M1 activation involves Stat1 activation, while much of the effect of M2 activation centers on Stat6 (27).…”