Myxoma virus selectively disrupts type I interferon signaling in primary human fibroblasts by blocking the activation of the Janus kinase Tyk2.
Poxviruses currently are known to disrupt Jak-STAT signal transduction induced by interferon (IFN) through two distinct mechanisms: (1) secreted poxviral IFN decoy receptors that prevent the initiation of IFN signaling from type I or II receptors at the cell surface; and (2) poxviral phosphatase that dephosphorylates STAT1 intracellularly. Here, we report a novel mechanism by which poxviruses can inhibit Jak-STAT signaling in response to type I IFN. Myxoma virus (MV) is a highly species-restricted member of the poxvirus family that infects only rabbits under the natural setting. Interestingly, primary human fibroblasts support a permissive MV infection that is only partially sensitive to the antiviral state induced by type I IFN. In this study we show that when type I IFN is added to primary human fibroblasts following MV infection, the tyrosine phosphorylation of the Janus kinase Tyk2 is specifically blocked, thereby preventing the subsequent activation of downstream STAT1 and STAT2. In stark contrast, type II IFN-induced activation of Jak1, Jak2 and STAT1 remains largely unaffected in MV-infected human fibroblasts. Unlike the de-activation of STAT1 by the poxvirus phosphatase, which is delivered into the cell by the input virions, the Tyk2 inhibition by MV infection requires new viral gene expression. Thus, our study documents a previously unrecognized immune evasion mechanism exploited by a poxvirus to selectively disrupt the type I IFN-Jak-STAT signaling cascade.
Wang
Fuan
F
BioTherapeutics Research Group, Robarts Research Institute, and Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada N6G 2V4.
Barrett
John W
JW
Shao
Qing
Q
Gao
Xiujuan
X
Dekaban
Gregory A
GA
McFadden
Grant
G
D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D009233:Myxoma virus / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011213:Poxviridae Infections / Q000503:physiopathology*; D011485:Protein Binding; D021381:Protein Transport; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D053634:TYK2 Kinase / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000503:physiopathology*; D014443:Tyrosine / Q000378:metabolism
D007370:Interferon Type I; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014443:Tyrosine; D053634:TYK2 Kinase