title: 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.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Marieke C
authors.initials: MC
authors.lastname: Verweij
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Wellish
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Travis
authors.initials: T
authors.lastname: Whitmer
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Malouli
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Martin
authors.initials: M
authors.lastname: Lapel
authors.affiliation: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
authors.forename: Stipan
authors.initials: S
authors.lastname: Jonjić
authors.affiliation: Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Juergen G
authors.initials: JG
authors.lastname: Haas
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Victor R
authors.initials: VR
authors.lastname: DeFilippis
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Mahalingam
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Klaus
authors.initials: K
authors.lastname: Früh
mesh_terms: D000818:Animals; D002460:Cell Line; D016663:Cercopithecinae; D002644:Chickenpox / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004274:DNA, Recombinant / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D014645:Herpesvirus 3, Human / Q000276:immunology / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D011994:Recombinant Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018140:Varicellovirus / Q000276:immunology / Q000502:physiology*
chemical_list: D004274:DNA, Recombinant; D017874:Immediate-Early Proteins; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D053612:Janus Kinases; D046988:Proteasome Endopeptidase Complex