title: Gamma interferon-induced interferon regulatory factor 1-dependent antiviral response inhibits vaccinia virus replication in mouse but not human fibroblasts.
abstract: Vaccinia virus (VACV) replicates in mouse and human fibroblasts with comparable kinetics and efficiency, yielding similar titers of infectious progeny. Here we demonstrate that gamma interferon (IFN-gamma) but not IFN-alpha or IFN-beta pretreatment of mouse fibroblasts prior to VACV infection induces a long-lasting antiviral state blocking VACV replication. In contrast, high doses of IFN-gamma failed to establish an antiviral state in human fibroblasts. In mouse fibroblasts, IFN-gamma impeded the viral replication cycle at the level of late gene transcription and blocked the multiplication of VACV genomes. The IFN-gamma-induced antiviral state invariably prevented the growth of different VACV strains but was not effective against the replication of ectromelia virus. The IFN-gamma effect required intact IFN-gamma receptor signaling prior to VACV infection through Janus kinase 2 (Jak2) and signal transducer and activator of transcription 1 (STAT1). The permissive state of IFN-gamma-treated human cells was unrelated to the VACV-encoded IFN decoy receptors B8 and B18 and associated with a complete disruption of STAT1 homodimer formation and DNA binding. Unlike human fibroblasts, mouse cells responded with long-lasting STAT1 activation which was preserved after VACV infection. The deletion of the IFN regulatory factor 1 (IRF-1) gene from mouse cells rescued efficient VACV replication, demonstrating that IRF-1 target genes have a critical role in VACV control. These data have implications for the understanding of VACV pathogenesis and identify an incongruent IFN-gamma response between the human host and the mouse model.
authors.affiliation: Heinrich-Heine-Universität, Institut für Virologie, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Trilling
authors.forename: Vu Thuy Khanh
authors.initials: VT
authors.lastname: Le
authors.forename: Albert
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Holger
authors.initials: H
authors.lastname: Ludwig
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hengel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis; D004481:Ectromelia virus / Q000502:physiology; D005347:Fibroblasts / Q000821:virology*; D017353:Gene Deletion; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014616:Vaccinia virus / Q000276:immunology* / Q000502:physiology*; D014779:Virus Replication; D000096743:Interferon gamma Receptor
chemical_list: D004279:DNA, Viral; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D053614:Janus Kinase 2; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494257:IRF1 protein, human; C494258:Irf1 protein, mouse; C494080:Stat1 protein, mouse; C507926:Jak2 protein, mouse