Investigating the production of viral double-stranded RNA and its effects on the innate antiviral immune response in fish

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The long-term goal of my research program is to study the innate immune response to virus infections in aquatic animals. Fish farming is an important contributor to Canada's economy; however, in recent years it has been plagued by untreatable viral outbreaks that destroy entire populations causing significant economic loss. Although fish have an immune system to protect themselves from virus infections, it is not always effective on its own due to virus evasion mechanisms. A promising therapy strategy is to trigger innate immune defenses already in place in the animal to block virus replication. The present research proposal aims to understand the fish innate immune response to viral double-stranded (ds)RNA. All viruses make dsRNA when they replicate in a cell, and this dsRNA acts as a 'flag' to the cell, to indicate that it is infected with a virus. Cells make type I interferon (IFN) when they sense dsRNA; these IFNs induce the expression of interferon-stimulated genes (ISGs) whose actions protect the cell by blocking virus replication. It has been previously shown that fish cells make IFN and ISGs in response to a synthetic dsRNA molecule, poly IC. However, no one has characterized the actual native dsRNA molecule produced by a fish virus in a fish cell, and these molecules have the potential to be the most important regulators of antiviral responses. This grant is proposing to show definitively that fish viruses produce dsRNA and to begin its characterization. We will also investigate how dsRNA enters a fish cell and whether it is able to induce IFNs and ISGs similar to what has been previously described with poly IC. From what little is known of viral dsRNA, it appears to act differently than poly IC. This is important because poly IC-based drugs have severe side effects in clinical trials. A better understanding of viral dsRNA could provide information for designing better dsRNA therapeutics with fewer side effects. In summary, this proposal can contribute to the development of new strategies for combating virus infections in fish and provide insight into the evolution of antiviral mechanisms in humans. In Canada the importance of fish viral infections has been illustrated by recent incidents of viral fish kills on both coasts as well as in the Great Lakes.