Mechanisms of innate immunity in bony fish

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In all multicellular organisms, the innate immune system acts to maintain homeostasis and defend against pathogens. In aquaculture setting, fish are especially susceptible to a variety of pathogens due to stress and crowded conditions. Despite the importance of innate immunity in host defense against pathogens, little is known about the mechanisms of fish innate immunity compared to those of mammals. **An important component of innate host defence and homeostasis are cells of myeloid lineage. Relatively little is known about the factors that mediate myeloid cell development (myelopoiesis) in bony fish, thus limiting our understanding of homeostatic processes and immune system disruption in response to pathogens. The first objective of the proposed research program is to characterize the interactions between myeloid growth factors, transcription factors and microRNAs during early myelopoiesis at a single cell and at cell population levels. To accomplish this objective, we propose to use a unique goldfish primary kidney macrophage culture system and recombinant goldfish macrophage growth factors and their receptors that we characterized during tenure of a previous NSERC Discovery grant. **In response to infection, central cells of innate immunity called macrophages, utilize a number of different antimicrobial mechanisms that inhibit microbial replication and contribute to the elimination of pathogens. In contrast to the large body of information regarding the mechanisms that control mammalian macrophage antimicrobial responses, relatively little is known about cytokine regulation of bony fish macrophage antimicrobial functions. The second objective of the proposed research program is to examine the regulation of antimicrobial responses of macrophages. We propose to examine the recognition of intracellular (Mycobacterium marinum, Aeromonas salmonicida) and extracellular (Trypanosoma carassii) fish pathogens by cytosolic pattern recognition receptors, and regulation of goldfish macrophage antibacterial responses by goldfish Type II interferons.**We are in an excellent position to address both objectives because we (a) developed procedures for generation and cultivation of primary macrophages from the goldfish; (b) established three in vitro and in vivo goldfish pathogen model systems (M. marinum, A. salmonicida and T. carassii); and (c) generated and validated goldfish-specific reagents and a panel of assays that enable both single-cell and cell population assessments of gene expression, proliferation, differentiation and function.**Due to depletion of natural fish stocks, the aquaculture industry in Canada has been growing at a rate of more that 20% per year. This research will contribute to our basic knowledge of the mechanisms of innate host defense in bony fish that is absolutely required for design of prevention strategies against fish infectious diseases.