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Permanent link (DOI): https://doi.org/10.7939/R3P337

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The analysis of cytokine regulation of macrophage antimicrobial responses of the goldfish (Carassius auratus L.) Open Access

Descriptions

Other title
Subject/Keyword
Inflammation
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Grayfer, Leon
Supervisor and department
Dr. Miodrag Belosevic (Department of Biological Sciences)
Examining committee member and department
Dr. Brian Dixon (Department of Biology, University of Waterloo)
Dr. Greg G. Goss (Department of Biological Sciences)
Dr. Declan Ali (Department of Biological Sciences)
Dr. Catherine J. Field (Department of Agricultural, Food & Nutritional Science)
Department
Department of Biological Sciences
Specialization

Date accepted
2011-06-17T19:11:26Z
Graduation date
2011-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Inflammation is a highly regulated immune response to tissue damage, infiltrating pathogens or both. Cells of the myeloid lineage such as macrophages are indispensable for the initiation, progression and resolution of inflammation. Macrophages possess an armamentarium of antimicrobial responses that are under cytokine regulation. The key inflammatory cytokines have been extensively characterized in mammals and their homologues have been identified across bony fish (teleosts). However, the specific functional roles of these teleost inflammatory cytokines have not been extensively studied. My doctoral research focused on characterizing the roles of key goldfish (Carassius auratus L.) inflammatory cytokines in the regulation of macrophage antimicrobial processes and in host defense against the fish pathogen, Mycobacterium marinum. I examined at the molecular and functional levels major goldfish pro-inflammatory cytokines TNFα, IFNγ, IFNγrel, their cognate receptors as well as the anti-inflammatory cytokine, IL-10. I also assessed the inflammatory mechanisms governing the antithesis of antimicrobial defenses and pathogen evasion during M. marinum infections of goldfish monocytes and macrophages. Unlike mammals, goldfish possess two Type II interferons, IFNγ and IFNγ related protein (IFNγrel). I established that zebrafish and goldfish also possess two interferon gamma receptor 1 chains (IFNGR1-1 and IFNGR1-2), where the goldfish rgIFNγ strictly bound rgIFNGR1-2 while rgIFNγrel exclusively engaged rgIFNGR1-1. Furthermore, rgIFNγ and rgIFNγrel elicited distinct antimicrobial responses and immune gene expression patterns in goldfish monocytes and macrophages. While the recombinant goldfish tumor necrosis factor alpha (rgTNFα) exhibited pro-inflammatory roles attributed to its mammalian counterpart, goldfish TNFα ligands (rgTNFα1 and rgTNFα2) and receptors (rgTNF-R1 and rgTNF-R2) formed dimers and not trimers, as in mammals. In the first functional analysis of a teleost interleukin-10, I demonstrated that rgIL-10 conferred anti-inflammatory properties towards goldfish monocytes. M. marinum infections of goldfish monocytes and macrophages ablated their cytokine-induced antimicrobial responses through several mechanisms. Intermittently, infected monocytes and macrophages increased their expression of pro-inflammatory genes while cells activated with rgTNFα2, rgIFNγ, or rgIFNγrel exhibit decreased viability of infecting M. marinum. Together, these findings provide an in vitro model system for investigating cytokine regulation of monocyte/macrophage antimicrobial responses and mycobacterium-host cell immune interactions of a lower vertebrate species.
Language
English
DOI
doi:10.7939/R3P337
Rights
License granted by Leon Grayfer (leonb@ualberta.ca) on 2011-06-17T16:13:36Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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