Characterization of the antiviral effects of interferon-α against a SARS-like coronoavirus infection in vitro

Abstract

Cell Research | www.cell-research.com Antiviral effects of IFN-α against MHV-1 220 npg ORIGINAL ARTICLE IntroductionIn March 2003, a number of laboratories independently reported the isolation and characterization of a novel coronavirus (CoV) from specimens of patients with severe acute respiratory syndrome (SARS) [1,2]. Although an effective therapeutic strategy against SARS has yet to be developed, interferons (IFN) are recognized to play critical roles in host resistance to viral infection [3][4][5][6], thereby implicating them as potential candidates for SARS CoV treatment. IFNs inhibit viral infection by directly interfering with viral replication and by inducing both an innate and adaptive immune response to infection. IFN-αs are effective in the treatment of hepatitis B and C [7,8] and respiratory coronavirus infections unrelated to the Urbani strain of SARS-CoV [9][10][11][12]. , and combinations of 18] are effective in inhibiting SARS-CoV replication in vitro. Moreover, it was reported that macacque monkeys were protected from infection with SARS CoV by treatment with .IFN alfacon-1 (Infergen, Intermune Corp, Brisbane, California), a synthetic IFN-α designed to represent a consensus , has been shown in both cell culture systems [21] and comparative clinical trials [22] to inhibit viral replication more potently than other IFN-αs. Based on these findings, a pilot study to evaluate the potential clinical benefit and safety of IFN alfacon-1 in SARS treatment was conducted by our laboratory. Interferon (IFN)-αs 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-α 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) d 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-αs. 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...

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