title: Comparative analysis of poxvirus orthologues of the vaccinia virus E3 protein: modulation of protein kinase R activity, cytokine responses, and virus pathogenicity.
abstract: Poxviruses are important human and animal pathogens that have evolved elaborate strategies for antagonizing host innate and adaptive immunity. The E3 protein of vaccinia virus, the prototypic member of the orthopoxviruses, functions as an inhibitor of innate immune signaling and is essential for vaccinia virus replication in vivo and in many human cell culture systems. However, the function of orthologues of E3 expressed by poxviruses of other genera with different host specificity remains largely unknown. In the present study, we characterized the E3 orthologues from sheeppox virus, yaba monkey tumor virus, swinepox virus, and myxoma virus for their ability to modulate protein kinase R (PKR) function, cytokine responses and virus pathogenicity. We found that the E3 orthologues of myxoma virus and swinepox virus could suppress PKR activation and interferon (IFN)-induced antiviral activities and restore the host range function of E3 in HeLa cells. In contrast, the E3 orthologues from sheeppox virus and yaba monkey tumor virus were unable to inhibit PKR activation. While the sheeppox orthologue was unable to restore the host range function of E3, the yaba monkey tumor virus orthologue partially restored E3-deficient vaccinia virus replication in HeLa cells, correlated with its ability to suppress IFN-induced antiviral activities. Moreover, poxvirus E3 orthologues show varying ability to inhibit the induction of antiviral and proinflammatory cytokines. Despite these in vitro results, none of the E3 orthologues tested was capable of restoring pathogenicity to E3-deficient vaccinia virus in vivo.
authors.affiliation: National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, Manitoba R3E 3R2, Canada.
authors.forename: Chad
authors.initials: C
authors.lastname: Myskiw
authors.forename: Janilyn
authors.initials: J
authors.lastname: Arsenio
authors.forename: Craig
authors.initials: C
authors.lastname: Hammett
authors.forename: Rebekah
authors.initials: R
authors.lastname: van Bruggen
authors.forename: Yvon
authors.initials: Y
authors.lastname: Deschambault
authors.forename: Nicole
authors.initials: N
authors.lastname: Beausoleil
authors.forename: Shawn
authors.initials: S
authors.lastname: Babiuk
authors.forename: Jingxin
authors.initials: J
authors.lastname: Cao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D006224:Cricetinae; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014615:Vaccinia / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; C081374:E3L protein, Vaccinia virus; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014764:Viral Proteins; D019892:eIF-2 Kinase