Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier.
Myxoma virus, a member of the poxvirus family, causes lethal infection only in rabbits, but the mechanism underlying the strict myxoma virus species barrier is not known. Here we show that myxoma virus infection of primary mouse embryo fibroblasts elicited extracellular signal-regulated kinase (Erk) signaling, which was integrated to interferon regulatory factor 3 activation and type I interferon induction. We further show that Erk inactivation or disruption of interferon signaling mediated by the transcription factor STAT1 broke the cellular blockade to myxoma virus multiplication. Moreover, STAT1 deficiency rendered mice highly susceptible to lethal myxoma virus infection. Thus, the Erk-interferon-STAT1 signaling cascade elicited by myxoma virus in nonpermissive primary mouse embryo fibroblasts mediates an innate cellular barrier to poxvirus infection.
Wang
Fuan
F
Robarts Research Institute, and Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario N6G 2V4, Canada.
Ma
Yiyue
Y
Barrett
John W
JW
Gao
Xiujuan
X
Loh
Joy
J
Barton
Erik
E
Virgin
Herbert W
HW
McFadden
Grant
G
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009233:Myxoma virus / Q000276:immunology / Q000502:physiology*; D010766:Phosphorylation; D011213:Poxviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D050794:STAT1 Transcription Factor; D013045:Species Specificity; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D019892:eIF-2 Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases