Characterization of the antiviral effects of interferon-alpha against a SARS-like coronoavirus infection in vitro.
Interferon (IFN)-alphas bind to and activate their cognate cell surface receptor to invoke an antiviral response in target cells. Well-described receptor-mediated signaling events result in transcriptional regulation of IFN sensitive genes, effectors of this antiviral response. Results from a pilot study to evaluate the clinical efficacy of IFN-alpha treatment of SARS patients provided evidence for IFN-inducible resolution of disease. In this report we examined the contribution of IFN-inducible phosphorylation-activation of specific signaling effectors to protection from infection by a SARS-related murine coronavirus, MHV-1. As anticipated, the earliest receptor-activation event, Jak1 phosphorylation, is critical for IFN-inducible protection from MHV-1 infection. Additionally, we provide evidence for the contribution of two kinases, the MAP kinase p38MAPK, and protein kinase C (PKC) delta to antiviral protection from MHV-1 infection. Notably, our data suggest that MHV-1 infection, as for the Urbani SARS coronoavirus, inhibits an IFN response, inferred from the lack of activation of pkr and 2'5'-oas, genes associated with mediating the antiviral activities of IFN-alphas. To identify potential target genes that are activated downstream of the IFN-inducible signaling effectors we identified, and that mediate protection from coronavirus infection, we examined the gene expression profiles in the peripheral blood mononuclear cells of SARS patients who received IFN treatment. A subset of differentially regulated genes were distinguished with functional properties associated with antimicrobial activities.
Department of Immunology, University of Toronto, Toronto, Ontario, M5G 2M1, Canada.
Joanna
J
Zorzitto
Carole L
CL
Galligan
Joanna J M
JJ
Ueng
Eleanor N
EN
Fish
D000818:Animals; D000998:Antiviral Agents / Q000276:immunology / Q000627:therapeutic use; D002460:Cell Line; D018352:Coronavirus Infections / Q000188:drug therapy / Q000276:immunology; D004791:Enzyme Inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000627:therapeutic use; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D006517:Murine hepatitis virus / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases