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

Marieke Verweij, Mary Wellish, Travis Whitmer, Daniel Malouli, Martin Lapel, Stipan Jonjić, Juergen G. Haas, Victor De Filippis, Ravi Mahalingam, Klaus Frueh

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1004901
JournalPLoS Pathogens
Volume11
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Chickenpox
Human Herpesvirus 3
Interferons
Viruses
Phosphorylation
Interferon Type I
Viral Proteins
Sensory Ganglia
Genes
Tetrahydrofolate Dehydrogenase
Proteins
Immediate-Early Genes
Herpes Zoster
Virus Diseases
Proteasome Endopeptidase Complex
Virus Replication
Macaca mulatta
Signal Transduction
Animal Models
Fibroblasts

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms. / Verweij, Marieke; Wellish, Mary; Whitmer, Travis; Malouli, Daniel; Lapel, Martin; Jonjić, Stipan; Haas, Juergen G.; De Filippis, Victor; Mahalingam, Ravi; Frueh, Klaus.

In: PLoS Pathogens, Vol. 11, No. 5, e1004901, 01.05.2015.

Research output: Contribution to journalArticle

Verweij, M, Wellish, M, Whitmer, T, Malouli, D, Lapel, M, Jonjić, S, Haas, JG, De Filippis, V, Mahalingam, R & Frueh, K 2015, 'Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms', PLoS Pathogens, vol. 11, no. 5, e1004901. https://doi.org/10.1371/journal.ppat.1004901
Verweij M, Wellish M, Whitmer T, Malouli D, Lapel M, Jonjić S et al. Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms. PLoS Pathogens. 2015 May 1;11(5). e1004901. https://doi.org/10.1371/journal.ppat.1004901
Verweij, Marieke ; Wellish, Mary ; Whitmer, Travis ; Malouli, Daniel ; Lapel, Martin ; Jonjić, Stipan ; Haas, Juergen G. ; De Filippis, Victor ; Mahalingam, Ravi ; Frueh, Klaus. / Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms. In: PLoS Pathogens. 2015 ; Vol. 11, No. 5.
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