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Journal of Virology, February 2005, p. 2079-2086, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2079-2086.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of Beta Interferon Induction by Severe Acute Respiratory Syndrome Coronavirus Suggests a Two-Step Model for Activation of Interferon Regulatory Factor 3

Martin Spiegel,1 Andreas Pichlmair,1 Luis Martínez-Sobrido,2 Jerome Cros,2 Adolfo García-Sastre,2 Otto Haller,1 and Friedemann Weber1*

Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Freiburg, Germany,1 Department of Microbiology, Mount Sinai School of Medicine, New York, New York2

Received 7 June 2004/ Accepted 20 September 2004

Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus termed SARS-CoV. We and others have previously shown that the replication of SARS-CoV can be suppressed by exogenously added interferon (IFN), a cytokine which is normally synthesized by cells as a reaction to virus infection. Here, we demonstrate that SARS-CoV escapes IFN-mediated growth inhibition by preventing the induction of IFN-ß. In SARS-CoV-infected cells, no endogenous IFN-ß transcripts and no IFN-ß promoter activity were detected. Nevertheless, the transcription factor interferon regulatory factor 3 (IRF-3), which is essential for IFN-ß promoter activity, was transported from the cytoplasm to the nucleus early after infection with SARS-CoV. However, at a later time point in infection, IRF-3 was again localized in the cytoplasm. By contrast, IRF-3 remained in the nucleus of cells infected with the IFN-inducing control virus Bunyamwera delNSs. Other signs of IRF-3 activation such as hyperphosphorylation, homodimer formation, and recruitment of the coactivator CREB-binding protein (CBP) were found late after infection with the control virus but not with SARS-CoV. Our data suggest that nuclear transport of IRF-3 is an immediate-early reaction to virus infection and may precede its hyperphosphorylation, homodimer formation, and binding to CBP. In order to escape activation of the IFN system, SARS-CoV appears to block a step after the early nuclear transport of IRF-3.

* Corresponding author. Mailing address: Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, D-79008 Freiburg, Germany. Phone: 49-761-203-6614. Fax: 49-761-203-6562. E-mail: friedemann.weber{at}uniklinik-freiburg.de.

Journal of Virology, February 2005, p. 2079-2086, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2079-2086.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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