Fever integrates antimicrobial defences, inflammation control, and tissue repair in a cold-blooded vertebrate

Abstract

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 programmes controlling core body temperature and the physiological stress that results from their disruption. Thus, we took advantage of a cold-blooded teleost fish that offered natural kinetics for the induction and regulation of fever and a broad range of tolerated temperatures. A custom swim chamber, coupled to high-fidelity quantitative positional tracking, showed remarkable consistency in fish behaviours and defined the febrile window. Animals exerting fever engaged pyrogenic cytokine gene programmes in the central nervous system, increased efficiency of leukocyte recruitment into the immune challenge site, and markedly improved pathogen clearance in vivo, even when an infecting bacterium grew better at higher temperatures. Contrary to earlier speculations for global upregulation of immunity, we identified selectivity in the protective immune mechanisms activated through fever. Fever then inhibited inflammation and markedly improved wound repair. Artificial mechanical hyperthermia, often used as a model of fever, recapitulated some but not all benefits achieved through natural host-driven dynamic thermoregulation. Together, our results define fever as an integrative host response that regulates induction and resolution of acute inflammation, and demonstrate that this integrative strategy emerged prior to endothermy during evolution.

The telencephalon is a neuronal substrate for systemic inflammatory responses in teleosts via polyamine metabolism

“…Behavioral fever is teleosts has been demonstrated in several models including viral and bacterial infections, killed bacterial challenges, and exposure to inflammatory agents like LPS or zymosan (30, 32, 33). However, whether the presence of microbiota in the systemic compartment induces behavioral fever in teleosts is currently unknown.…”

“…These results suggest that polyamines derived from systemic bacteria and/or from the bacteria that penetrate the Tel directly modulate pyrogenic cytokine responses in the Tel but not the Hyp. Systemic bacteria induce behavioral fever in rainbow trout in a polyamine-dependent manner Behavioral fever is teleosts has been demonstrated in several models including viral and bacterial infections, killed bacterial challenges, and exposure to inflammatory agents like LPS or zymosan (30,32,33). However, whether the presence of microbiota in the systemic compartment induces behavioral fever in teleosts is currently unknown.…”

“…Video recording was achieved using Bandicam software (Bandicam Company, USA). The analysis of recorded videos was performed with Ethovision XT, Version 11 (Noldus, Wageningen, Netherlands), allowing for the quantification of behavioral parameters such as changes in thermal preference, swimming velocity, and the frequency of transitions between thermal zones as previously described (33).…”

“…Similar to mammals, systemic and brain increases in pyrogenic cytokines like IL1β, TNFα, and IL6, alongside PGE2, have been identified as key players in teleosts behavioral fever responses. Furthermore, the preoptic area of the hypothalamus (POA) is thought to be, as in mammals, the main brain region responding to systemic infection and driving behavioral fever responses in ectotherms (30,(33)(34)(35). Yet, expression of the prostaglandin receptor EP3 was detected in the telencephalon and optic lobe of Atlantic salmon (29), suggesting that other brain regions detect systemic inflammation in teleosts.…”

“…For instance, teleosts become lethargic, stop feeding and seek warmer water temperatures in a process known as behavioral fever (27)(28)(29)(30)(31)(32). This behaviorally induced fever provides a survival advantage, as it enhances the immune system's efficacy, hinders the proliferation of pathogens and resolves wound healing more effectively (27,28,(31)(32)(33). Similar to mammals, systemic and brain increases in pyrogenic cytokines like IL1β, TNFα, and IL6, alongside PGE2, have been identified as key players in teleosts behavioral fever responses.…”