Gamma interferon-induced interferon regulatory factor 1-dependent antiviral response inhibits vaccinia virus replication in mouse but not human fibroblasts.
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.
Trilling
Mirko
M
Heinrich-Heine-Universität, Institut für Virologie, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Le
Vu Thuy Khanh
VT
Zimmermann
Albert
A
Ludwig
Holger
H
Pfeffer
Klaus
K
Sutter
Gerd
G
Smith
Geoffrey L
GL
Hengel
Hartmut
H
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
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