Inhibition of Beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3.
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-beta. In SARS-CoV-infected cells, no endogenous IFN-beta transcripts and no IFN-beta promoter activity were detected. Nevertheless, the transcription factor interferon regulatory factor 3 (IRF-3), which is essential for IFN-beta 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.
Spiegel
Martin
M
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, D-79008 Freiburg, Germany.
Pichlmair
Andreas
A
Martínez-Sobrido
Luis
L
Cros
Jerome
J
García-Sastre
Adolfo
A
Haller
Otto
O
Weber
Friedemann
F
D000818:Animals; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000378:metabolism*; D010766:Phosphorylation; D045473:Severe acute respiratory syndrome-related coronavirus / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014709:Vero Cells
D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D014157:Transcription Factors; D016899:Interferon-beta