Orf virus inhibits interferon stimulated gene expression and modulates the JAK/STAT signalling pathway

• Published in: Virus research Vol. 208; pp. 180 - 188
• Main Authors: Harvey, Ryan, McCaughan, Catherine, Wise, Lyn M., Mercer, Andrew A., Fleming, Stephen B.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 02.10.2015
• Subjects: Cell Line; GTP-Binding Proteins - metabolism; HeLa Cells; Host-Pathogen Interactions; Humans; Immuno-modulation; Interferon; Interferons - metabolism; JAK/STAT signalling pathway; Janus Kinases - genetics; Janus Kinases - metabolism; Myxovirus Resistance Proteins - metabolism; Orf virus; Orf virus - genetics; Orf virus - metabolism; Parapoxvirus; Phosphorylation; Poxviridae Infections - genetics; Poxviridae Infections - metabolism; Poxvirus; Signal Transduction; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Vaccinia virus; Viral Proteins - genetics; Viral Proteins - metabolism; Immuno-modulation; JAK/STAT signalling pathway; Interferon; Orf virus; Parapoxvirus
• DOI: 10.1016/j.virusres.2015.06.014
• ISSN: 0168-1702

•The parapoxvirus, orf virus, inhibits interferon stimulated gene (ISG) expression.•Orf virus inhibits ISG expression induced by type I and type II IFNs.•Orf virus modulates the JAK/STAT signalling pathway by dephosphorylating STAT1.•New viral protein expression is not required to dephosphorylate STAT1. Interferons (IFNs) play a critical role as a first line of defence against viral infection. Activation of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway by IFNs leads to the production of IFN stimulated genes (ISGs) that block viral replication. The Parapoxvirus, Orf virus (ORFV) induces acute pustular skin lesions of sheep and goats and is transmissible to man. The virus replicates in keratinocytes that are the immune sentinels of skin. We investigated whether or not ORFV could block the expression of ISGs. The human gene GBP1 is stimulated exclusively by type II IFN while MxA is stimulated exclusively in response to type I IFNs. We found that GBP1 and MxA were strongly inhibited in ORFV infected HeLa cells stimulated with IFN-γ or IFN-α respectively. Furthermore we showed that ORFV inhibition of ISG expression was not affected by cells pretreated with adenosine N1-oxide (ANO), a molecule that inhibits poxvirus mRNA translation. This suggested that new viral gene synthesis was not required and that a virion structural protein was involved. We next investigated whether ORFV infection affected STAT1 phosphorylation in IFN-γ or IFN-α treated HeLa cells. We found that ORFV reduced the levels of phosphorylated STAT1 in a dose-dependent manner and was specific for Tyr701 but not Ser727. Treatment of cells with sodium vanadate suggested that a tyrosine phosphatase was responsible for dephosphorylating STAT1-p. ORFV encodes a factor, ORFV057, with homology to the vaccinia virus structural protein VH1 that impairs the JAK/STAT pathway by dephosphorylating STAT1. Our findings show that ORFV has the capability to block ISG expression and modulate the JAK/STAT signalling pathway.