Antiviral Activity of Salmonid Interferon Gamma against Infectious Pancreatic Necrosis Virus and Salmonid Alphavirus and its Dependency on Type I Interferon

This work explores antiviral activity and gene induction properties of interferon gamma (IFN-γ) compared to type I IFN (IFNa1) in Atlantic salmon. IFN-γ protected salmon cells against infectious pancreatic necrosis virus (IPNV) induced cytopathic effect (CPE), reduced viral titers and inhibited synthesis of the viral structural protein VP3. Moreover, IFN-γ showed potent antiviral activity against salmonid alphavirus 3 (SAV3) measured as reduction in virus nsP1 transcripts. IFN-γ (a type II IFN) had less specific antiviral activity against IPNV compared to IFNa1, showing an EC50 of 1.6 ng/ml versus 31 pg/ml in the CPE reduction assay. Compared to IFNa1, IFN-γ was a more effective inducer of the antiviral protein GBP, several interferon regulatory transcription factors (IRFs) and the chemokine IP-10. The antiviral activity of IFN-γ may also in part be ascribed to up-regulation of Mx, ISG15, and viperin. These are typical type I IFN induced genes in mammals and were also more strongly induced by IFNa1 than IFN-γ in salmon cells. Fish and mammalian IFN-γ thus show strikingly similar gene induction properties. Interestingly, the antiviral activity of IFN-γ against IPNV and SAV3, and its ability to induce Mx and ISG15 markedly decreased in the presence of neutralizing antiserum against IFNa1. In contrast, antiIFNa1 had no effect on the induction of IRF-1 and IP-10 by IFN-γ. This suggests that the antiviral activity of IFN-γ is partially dependent on IFNa induction. However, because antiIFNa1 could not abolish IFN-γ mediated induction of Mx and ISG15 completely, IFN-γ may possibly also induces such genes directly. INTRODUCTION Interferons (IFN) were originally identified as proteins that induce an antiviral state in cells, but they also have important regulatory functions in the immune system (51). Type I IFN (predominantly IFN-α and IFN-β) and type II IFN (IFN-γ) play critical roles in innate and adaptive immune response against viral infection in vertebrates (30, 32). In mammals, IFN-α/β are produced by most cells upon virus infection. In contrast, IFN-γ is produced primarily by natural killer (NK) cells during innate responses, and by CD4 + T helper 1 (Th1) cells and CD8 + cytotoxic T cells during adaptive immune responses (44). IFN-γ is regarded as the typical Th1 cytokine because it directs differentiation of naïve CD4 + cells toward a Th1 phenotype and is a major product of Th1 cells (45). on O cber 0, 2017 by gest http/jvi.asm .rg/ D ow nladed fom