Examination of the effects of fever on inflammation and tissue repair in fish
Creators: Haddad, Farah
Publisher: name: University of Alberta Library
Year: 2024

<p>Fever has long been recognized as a general inflammatory response and physiological defense mechanism to viral, bacterial, and fungal infections associated with a rise in the host’s temperature. It is also considered a behavioural and complex neuroendocrine response most vertebrates use to help their immune system beat infections. However, fever is commonly regarded as a deleterious symptom of inflammation rather than a mechanism of defense and protection and is often suppressed using antipyretics. The febrile response is largely conserved for over 555 million years of metazoan evolution in both endotherms and ectotherms with shared common pathways for fever induction. Yet, we continue to debate whether it is net positive or negative for host health because of important gaps in our understanding of its biology. Unlike warm-blooded vertebrates (i.e., endotherms), ectotherms or cold-blooded vertebrates rely on behaviour to regulate their body temperature by moving, for example, to warmer environments, and this has been observed in a vast range of species, including reptiles, amphibians, insects, crustaceans, and fish. Experimentally blocking fever, especially using nonsteroidal anti-inflammatory drugs (NSAIDs) in endothermic models, resulted in little understanding of the effects of fever on the immune system and its underlying mechanisms.  This further illustrates the utility of studying fever from a comparative approach using ectothermic models. Multiple lines of evidence support the value of moderate fever to host survival, but the mechanisms involved remain unclear. This is difficult to establish in warm-blooded animal models, given the strict programs controlling core body temperature and the physiological stress that results from their disruption. I hypothesized that the contributions of fever went beyond popular models of pathogen thermal restriction and global upregulation of immune antimicrobial defenses. <br>
For my thesis research, I took advantage of cold-blooded teleost fish models that offered natural kinetics for the induction and regulation of fever and a broad range of tolerated temperatures to overcome key limitations of mechanical and pharmacological manipulation of fever in endotherms. A custom swim chamber, coupled with high-fidelity quantitative positional tracking, showed remarkable consistency in fish behaviours and defined the febrile window. Zymosan-induced peritonitis and a live Aeromonas veronii cutaneous infection model were used to study the behavioral response using the Annular Temperature Preference Tank (ATPT) as a high-resolution custom setup. I found that the zymosan challenge led to increased temperature preference simultaneously with two lethargy behaviours indicated by a decrease in swimming velocity and migration rates across different thermal zones. Meanwhile, the behavioural thermoregulatory response against A. veronii was distinct from that against zymosan in terms of a longer duration of fever window and later timing of fever induction. These custom behavioural fever responses were paired with increased efficiency of leukocyte recruitment to the immune challenge site, early expression of proinflammatory cytokines, promotion of antimicrobial responses, rapid resolution of inflammation, and bacterial clearance compared to control fish held at standard housing temperatures. Fever then inhibited inflammation and markedly improved wound repair. My data shows that these custom fever responses following different immune challenges under natural conditions have greater benefits to the host than previously shown for fish innate immune responses. Overall, my findings showcase the immune-modulatory capacity of dynamic thermoregulation across fish (a Cyprinid and a salmonid) and show its potential value prior to the emergence of metabolic fever in evolution. Together, these results define fever as an integrative host response that regulates the induction and resolution of acute inflammation.</p>