Grant: Discovery Grants Program - Individual

The innate immune response is the first line of defense against invading viruses in animals, and provides broad-spectrum antiviral protection. Fish are no exception, indeed stimulating innate antiviral immunity is an excellent approach to developing novel antiviral therapies to protect farmed fish, which are economically important for Canada. The proposed research program aims to investigate three innate immune responses that have yet to be identified in fish in general and rainbow trout (Ontario's most common farmed fish) specifically. This work focuses on double-stranded (ds)RNA, produced by viruses during replication, which is a strong inducer of the keystone of innate antiviral immunity, type I interferons (IFNs). IFNs stimulate the production of IFN-stimulated genes (ISGs) that accumulate within the cell to form the antiviral state, a protective state that makes a cell refractive to virus infection. This pathway is known as the dsRNA-IFN-antiviral axis. The first aim of the present proposal will examine how to stimulate interferon production with dsRNA using a natural' method just recently discovered, namely using extracellular vesicles containing dsRNA . This method may prove to be optimal, as it would protect dsRNA from degradation and may reduce dsRNA's cytotoxic effects. The second aim will focus on understanding interferon effects within the cell, specifically looking at the function of two ISGs, vig-1 and vig-3. These genes are of interest because vig-3 itself and the product of vig-1 activity, 3'-deoxy-3', 4'-didehydro-CTP (ddhCTP), can be added to cells to enhance their innate antiviral activity. Thus understanding the function of these two ISGs may help develop novel antiviral treatments that could be given to fish to treat virus infections. The third aim will focus on trained immunity, which is immunological memory of the innate immune system. Antiviral trained immunity is not well understood; however, if properly activated, it would allow for young animals to be trained' or remember virus infections in order for them to mount enhanced antiviral responses later in life. The power of trained immunity is that it provides broad-spectrum vaccine strategies, as trained immunity protects an animal against viruses in general, as opposed to traditional vaccines that provide protection to a specific strain of virus. The proposed research program focuses on discovering novel pathways and responses within the dsRNA-IFN-antiviral axis that will not only provide fundamental insights but the knowledge base for the application of novel antiviral therapies in an economically relevant fish species.