Inhibition of interferons by ectromelia virus.
Ectromelia virus (EV) is an orthopoxvirus (OPV) that causes mousepox, a severe disease of laboratory mice. Mousepox is a useful model of OPV infection because EV is likely to be a natural mouse pathogen, unlike its close relatives vaccinia virus (VV) and variola virus. Several studies have highlighted the importance of mouse interferons (IFNs) in resistance to and recovery from EV infection, but little is known of the anti-IFN strategies encoded by the virus itself. We have determined that 12 distinct strains and isolates of EV encode soluble, secreted receptors for IFN-gamma (vIFN-gammaR) and IFN-alpha/beta (vIFN-alpha/betaR) that are homologous to those identified in other OPVs. We demonstrate for the first time that the EV vIFN-gammaR has the unique ability to inhibit the biological activity of mouse IFN-gamma. The EV vIFN-alpha/betaR was a potent inhibitor of human and mouse IFN-alpha and human IFN-beta but, surprisingly, was unable to inhibit mouse IFN-beta. The replication of all of the EVs included in our study and of cowpox virus was more resistant than VV to the antiviral effects induced in mouse L-929 cells by IFN-alpha/beta and IFN-gamma. Sequencing studies showed that this EV resistance is likely to be partly mediated by the double-stranded-RNA-binding protein encoded by an intact EV homolog of the VV E3L gene. The absence of a functional K3L gene, which encodes a viral eIF-2alpha homolog, in EV suggests that the virus encodes a novel mechanism to counteract the IFN response. These findings will facilitate future studies of the role of viral anti-IFN strategies in mousepox pathogenesis. Their significance in the light of earlier data on the role of IFNs in mousepox is discussed.
Smith
Vincent P
VP
Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
Alcami
Antonio
A
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D004481:Ectromelia virus / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D007739:L Cells; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D018155:Orthopoxvirus / Q000235:genetics / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D000998:Antiviral Agents; D004279:DNA, Viral; D015852:Eukaryotic Initiation Factor-2; D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D008565:Membrane Proteins; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D014764:Viral Proteins; D000096743:Interferon gamma Receptor; C446321:E3L protein, Ectromelia virus; C446320:K3L protein, Ectromelia virus