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Journal of Virology, April 2009, p. 3684-3695, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02042-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Gamma Interferon-Induced Interferon Regulatory Factor 1-Dependent Antiviral Response Inhibits Vaccinia Virus Replication in Mouse but Not Human Fibroblasts{triangledown}

Mirko Trilling,1 Vu Thuy Khanh Le,1 Albert Zimmermann,1 Holger Ludwig,2 Klaus Pfeffer,3 Gerd Sutter,2 Geoffrey L. Smith,4 and Hartmut Hengel1*

Institute for Virology,1 Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Düsseldorf, D-40225 Germany,3 Department of Virology, Paul-Ehrlich-Institut, Langen, D-63225 Germany,2 Department of Virology, Faculty of Medicine, Imperial College London, London, United Kingdom4

Received 27 September 2008/ Accepted 22 January 2009

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-β 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.

* Corresponding author. Mailing address: Heinrich-Heine-Universität, Institut für Virologie, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Phone: 49 2118112225. Fax: 49 2118110792. E-mail: hartmut.hengel{at}uni-duesseldorf.de

{triangledown} Published ahead of print on 11 February 2009.

Journal of Virology, April 2009, p. 3684-3695, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02042-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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