Induction of Atlantic salmon type I interferon and antagonism by infectious pancreatic necrosis virus

Viral infections are a leading cause of mortality in the farming of Atlantic salmon in Norway. Viral outbreaks cause heavy losses each year, and one of the most predominant viral diseases is infectious pancreatic necrosis (IPN). The virus causing this disease, the infectious pancreatic necrosis virus (IPNV), belongs to the Birnaviridae family of viruses with a double-stranded RNA (dsRNA) genome. Although viral disease is prevalent in the Atlantic salmon aquaculture industry, fish possess an immune system fully equipped to handle viral disease. In this work we have studied induction of the type I interferon (IFN) response in Atlantic salmon in response to intracellular foreign RNA. IFNs are pivotal alarm proteins alerting other cells of the infection, contributing to the establishment of an antiviral state. In order for IFNs to be produced, the cell must recognize the presence of the viral intruder. Viruses are recognized by a wide range of different receptors. The receptors recognize characteristic pathogen associated molecular patterns (PAMPs), for viruses usually the nucleic acids. The receptors proceed to signal through a conserved signaling pathway that culminates in the induction of IFN production. We have identified a central member of the signaling pathway, IPS-1, a signal mediator conserved through evolution. We have also investigated the promoter elements of two type I IFNa promoters, characterizing the regulatory regions. The induction of IFN production is a common target for viral proteins trying to subvert the IFN response and subsequent antiviral state. Using the IFN promoters and IPS-1 protein, we identified IFN antagonistic effects of separate IPNV proteins

Infectious pancreatic necrosis virus proteins VP2, VP3, VP4 and VP5 antagonize IFNa1 promoter activation while VP1 induces IFNa1

Published version. Source at http://doi.org/10.1016/j.virusres.2014.11.018.Infectious pancreatic necrosis virus (IPNV) is one of the major viral pathogens causing disease in farmed Atlantic salmon worldwide. In the present work we show that several of the IPN proteins have powerful antagonistic properties against type I IFN induction in Atlantic salmon. Each of the five IPNV genes cloned into an expression vector were tested for the ability to influence activation of the Atlantic salmon IFNa1 promoter by the interferon promoter inducing protein one (IPS-1) or interferon regulatory factors (IRF). This showed that preVP2,VP3 andVP5 inhibited activation of both promoters, whileVP4 only antagonized activation of the IFNa1 promoter. The viral protease VP4 was the most potent inhibitor of IFN induction, apparently targeting the IRF1 and IRF3 branch of the signaling cascade. VP4 antagonism is independent of its protease activity since the catalytically dead mutant VP4K674A inhibited activation of the IFNa1 promoter to a similar extent as wild type VP4. In contrast to the other IPNV proteins, the RNA-dependent RNA polymerase VP1 activated the IFNa1 promoter. The ability to activate the IFN response was disrupted in the mutant VP1S163A, which has lost the ability to produce dsRNA. VP1 also exhibited synergistic effects with IRF1 and IRF3 in inducing an IFNa1-dependent antiviral state in cells. Taken together these results suggest that IPNV has developed multiple IFN antagonistic properties to prevent IFN-induction by VP1 and its dsRNA genome