Molecular basis of antiviral immune responses in teleost fish

Eslamloo, Khalil (2019) Molecular basis of antiviral immune responses in teleost fish. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

In addition to the importance of Atlantic cod (Gadus morhua) and Atlantic salmon (Salmo salar) for fisheries or aquaculture of several countries including Canada, these species are valuable for comparative immunological studies. The Atlantic cod possesses a unique immune system among many teleosts, and the Atlantic salmon may serve as a molecular model for genomics studies in salmonids. Several aspects of the immune response in these species are yet to be determined, and a broader picture of the immune responses of Atlantic cod and Atlantic salmon may enhance the health management of wild or farmed populations of these species. With respect to the importance of macrophages in innate immune responses, the objectives of my thesis were to use a macrophage model and genomics approaches to enhance our understanding of the antiviral immune response of Atlantic cod, and to profile the transcriptome of the dietary fatty acid-dependent and antiviral responses of Atlantic salmon. In Chapter 2, I used microarray and quantitative reverse transcription-polymerase chain reaction (qPCR) analyses to identify and validate several antiviral biomarker genes encoding receptors, signal transducers, transcription factors and immune effectors in Atlantic cod macrophages. This study revealed that the antiviral immune responses of Atlantic cod macrophages may be activated downstream of RIG-I-like receptor (RLR)- and Toll-like receptor (TLR)-dependent pathways. Chapter 3 fully characterised Atlantic cod viperin, one of the putative interferon-stimulated genes (ISGs) identified in Chapter 2. I found Atlantic cod viperin to be an evolutionarily conserved gene with an antiviral response that is regulated through endosomal-TLRs-, protein kinase R (PKR), mitogen-activated protein kinase (MAPK)- and interferon (IFN)-mediated pathways. Using deep sequencing and gene expression analysis, Chapter 4 profiled the immune-related microRNAs (miRNAs) of Atlantic cod macrophages, and discovered both evolutionarily-conserved and teleost-specific miRNAs playing roles in the antiviral immune response of macrophages of this species. Concerning the immune-related functions of omega (n)-3 and n-6 fatty acids, Chapter 5 used an ex vivo model to evaluate if varying levels of dietary n-3 and n-6 fatty acids influence the antiviral responses of Atlantic salmon macrophage-like cells (MLCs). Chapter 5 showed that different levels of dietary n-3 and n-6 fatty acids change the fatty acid composition of head kidney leukocytes, and it identified fatty acid-dependent immune-related biomarkers in Atlantic salmon MLCs. Moreover, this chapter identified a large number of biomarker transcripts activated by RLR, TLR, MAPK and IFN pathways during the antiviral response of Atlantic salmon MLCs. This thesis contributed significantly to the development of a comprehensive picture of the genes, non-coding RNAs and regulating pathways involved in antiviral immune responses of teleosts. In addition, my thesis enhances the general understanding of the immunomodulatory functions of dietary n-3 fatty acids in Atlantic salmon. The novel results generated by this thesis contribute molecular biomarkers that may be used in future immunological studies to aid in the development of aquafeeds and other health management tools for teleosts.

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