Contributions of Fever to Tissue Repair in Teleost Fish
Creators: Sherif, Amro MS
Publisher: name: University of Alberta Library
Year: 2023

<p>Fever is a physiological defense mechanism against infection associated with a rise in host’s temperature. Febrile responses are evolutionarily conserved through millions of years, taking place in both warm-blooded and cold-blooded vertebrates that share common biochemical pathways for fever induction. Ectotherms, unlike endotherms, rely entirely on behaviour to raise their body temperatures by translocating to warmer environments. Despite fever’s long-standing role in host survival, as displayed in several animal experiments and clinical trials, the underlying mechanisms remain poorly understood. Historically, a shift away from a pathogen’s preferred temperature and global activation of the immune system were proposed. However, the reported capability of microbes to thrive at fever-range temperatures and detrimental inflammation-associated tissue damage in case of overall augmentation of immune responses undermine these assumptions. Therefore, a debate on the net value of fever to health continues to permeate the literature, which was further compounded by limitations in available experimental models effectively replicating natural physiological processes driving and maintaining fever. The commonly utilized endothermic models employing fever-range hyperthermia provided valuable insights into the thermal regulation of innate and adaptive immunity. However, physiological stress coupled with mechanical hyperthermia or off-target effects accompanying antipyretics use in these models intervened with intrinsic pathways, altering immune and homeostatic regulatory effects prompted by febrile responses. <br>
In this study, I took advantage of a cold-blooded teleost fish model with the advantage of natural kinetics for fever induction and regulation as well as wide-ranging tolerated temperatures to investigate the ability of a febrile response to enhance restoration of tissue integrity and homeostasis. A custom swim chamber, combined with high-resolution quantitative positional tracking, demonstrated consistency in the preference of infected fish for higher temperatures. A self-resolving Aeromonas veronii cutaneous infection allowed for examination of the impact of fever on inflammatory and subsequent proliferative phase of tissue repair that necessitates proper resolution of inflammation. This was achieved through in vivo and in vitro assays, including histopathological, gene expression, immune functional and proliferation analyses. <br>
Results reveal a novel intrinsic fever capacity to promote restoration of tissue homeostasis upon infection. Fish exerting behavioural fever demonstrated enhanced kinetics of leukocyte recruitment to the infection site and significantly improved bacterial clearance, despite A. veronii growing better at higher temperatures. We further characterized selectivity in the induction of protective immune mechanisms during febrile response that correlated less inflammation-associated collateral injury. Marked differences in the expression of inflammatory mediators were observed under fever and non-fever conditions. Additional robustness of inflammation control and upregulation of pro-resolution cytokines promoted the shift toward proliferation stage. Fever fish showed enhancements of wound closure, re-epithelialization and collagen deposition. These attributes were coupled with remarkable upregulation of growth factors and efficient epidermal and dermal healing. Fever-range hyperthermia, commonly used to study fever, and mechanical replication of behavioural fever’s thermal pattern recapitulated some but not all benefits achieved during natural host-driven dynamic thermoregulation. <br>
Together, my findings show that fever is not a by-product of inflammation but an integrative host response that regulates inflammatory and proliferative phases of tissue healing, contributing significantly to restoring tissue homeostasis subsequent to infection. They further underscore the significant role of febrile responses in host defense and provide a better understanding of fever biology and the underlying mechanisms of its survival capacity.    </p>