Blockade of interferon induction and action by the E3L double-stranded RNA binding proteins of vaccinia virus.
The vaccinia virus E3L gene encodes two double-stranded RNA binding proteins that promote viral growth and pathogenesis through suppression of innate immunity. To explore how E3L enables vaccinia virus to evade the interferon system, cells and mice deficient in the principal interferon-regulated antiviral enzymes, PKR and RNase L, were infected with wild-type vaccinia virus and strains of vaccinia virus from which E3L had been deleted (E3L-deleted strains). While wild-type virus was unaffected by RNase L and PKR, virus lacking E3L replicated only in the deficient cells. Nevertheless, E3L-deleted virus failed to replicate to high titers or to cause significant morbidity or mortality in triply deficient mice lacking RNase L, PKR, and Mx1. To investigate the underlying cause, we determined the effect of E3L on interferon regulatory factor 3 (IRF3), a transcription factor required for viral induction of subtypes of type I interferons. Results showed that IRF3 activation and interferon-beta induction occurred after infections with E3L-deleted virus but not with wild-type virus. These findings demonstrate that E3L plays an essential role in the pathogenesis of vaccinia virus by blocking the interferon system at multiple levels. Furthermore, our results indicate the existence of an interferon-mediated antipoxvirus pathway that operates independently of PKR, Mx1, or the 2-5A/RNase L system.
Xiang
Ying
Y
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Condit
Richard C
RC
Vijaysri
Sangeetha
S
Jacobs
Bertram
B
Williams
Bryan R G
BR
Silverman
Robert H
RH
D000818:Animals; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000276:immunology; D004195:Disease Models, Animal; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics; D005260:Female; D019204:GTP-Binding Proteins; D017353:Gene Deletion; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064547:Myxovirus Resistance Proteins; D011506:Proteins / Q000235:genetics; D016601:RNA-Binding Proteins / Q000276:immunology / Q000494:pharmacology*; D014157:Transcription Factors / Q000276:immunology; D014615:Vaccinia / Q000276:immunology / Q000821:virology*; D014616:Vaccinia virus / Q000378:metabolism / Q000472:pathogenicity*; D014764:Viral Proteins / Q000276:immunology / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000235:genetics
D004268:DNA-Binding Proteins; C081374:E3L protein, Vaccinia virus; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014764:Viral Proteins; D016899:Interferon-beta; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D019204:GTP-Binding Proteins