Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms.

Abstract

Varicella zoster virus (VZV) causes chickenpox in humans and, subsequently, establishes latency in the sensory ganglia from where it reactivates to cause herpes zoster. Infection of rhesus macaques with simian varicella virus (SVV) recapitulates VZV pathogenesis in humans thus representing a suitable animal model for VZV infection. While the type I interferon (IFN) response has been shown to affect VZV replication, the virus employs counter mechanisms to prevent the induction of anti-viral IFN stimulated genes (ISG). Here, we demonstrate that SVV inhibits type I IFN-activated signal transduction via the JAK-STAT pathway. SVV-infected rhesus fibroblasts were refractory to IFN stimulation displaying reduced protein levels of IRF9 and lacking STAT2 phosphorylation. Since previous work implicated involvement of the VZV immediate early gene product ORF63 in preventing ISG-induction we studied the role of SVV ORF63 in generating resistance to IFN treatment. Interestingly, SVV ORF63 did not affect STAT2 phosphorylation but caused IRF9 degradation in a proteasome-dependent manner, suggesting that SVV employs multiple mechanisms to counteract the effect of IFN. Control of SVV ORF63 protein levels via fusion to a dihydrofolate reductase (DHFR)-degradation domain additionally confirmed its requirement for viral replication. Our results also show a prominent reduction of IRF9 and inhibition of STAT2 phosphorylation in VZV-infected cells. In addition, cells expressing VZV ORF63 blocked IFN-stimulation and displayed reduced levels of the IRF9 protein. Taken together, our data suggest that varicella ORF63 prevents ISG-induction both directly via IRF9 degradation and indirectly via transcriptional control of viral proteins that interfere with STAT2 phosphorylation. SVV and VZV thus encode multiple viral gene products that tightly control IFN-induced anti-viral responses.

• Authors: Marieke C Verweij, Mary Wellish, Travis Whitmer, Daniel Malouli, Martin Lapel, Stipan Jonjić, Juergen G Haas, Victor R DeFilippis, Ravi Mahalingam, Klaus Früh
• Journal: PLoS pathogens (PLoS Pathog) Vol. 11 Issue 5 Pg. e1004901 (May 2015) ISSN: 1553-7374 [Electronic] United States
• PMID: 25973608 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Recombinant
• Immediate-Early Proteins
• Interferon Type I
• Interferon-Stimulated Gene Factor 3, gamma Subunit
• Recombinant Proteins
• STAT Transcription Factors
• Janus Kinases
• Proteasome Endopeptidase Complex

Topics

• Animals
• Cell Line
• Cercopithecinae
• Chickenpox (immunology, metabolism, pathology, virology)
• DNA, Recombinant (metabolism)
• Gene Expression Regulation, Viral
• Herpesviridae Infections (immunology, metabolism, pathology, virology)
• Herpesvirus 3, Human (immunology, physiology)
• Host-Pathogen Interactions
• Humans
• Immediate-Early Proteins (genetics, metabolism)
• Immunity, Innate
• Interferon Type I (antagonists & inhibitors, metabolism)
• Interferon-Stimulated Gene Factor 3, gamma Subunit (antagonists & inhibitors, genetics, metabolism)
• Janus Kinases (metabolism)
• Phosphorylation
• Proteasome Endopeptidase Complex
• Protein Processing, Post-Translational
• Proteolysis
• Recombinant Proteins (metabolism)
• STAT Transcription Factors (genetics, metabolism)
• Signal Transduction
• Varicellovirus (immunology, physiology)