Fever integrates antimicrobial defences, inflammation control, and tissue repair in a cold-blooded vertebrate
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eLife assessment
This study addressed a long-standing question in biology - the role of fever during infections. Using innovative research strategy, the authors provide compelling evidence for the positive impact of higher body temperature on both pathogen clearance and tissue repair. This study thus provides important advances in our understanding of host defense and its connection with physiology and behavior.
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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.
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Author Response
Reviewer #1 (Public Review):
- The role of increased temperature on immunity and homeostasis in cold-blooded vertebrates is an understudied yet important field. This work not only examines how immunity is impacted by fever, but also incorporates an infection model and examines resolution of the response. This work can serve as a model for other groups interested in the study of hyperthermia and immunity.
Thank you very much.
- Generally speaking, I agree with the authors' strategy and interpretations of the data.
- In the Introduction, the authors chose to begin with how fever in endotherms impact the immune system. Considering that this work exclusively examines the response of a teleost (goldfish), the authors might consider flipping the way they present this work. After all, cold-blooded vertebrates rely on this …
Author Response
Reviewer #1 (Public Review):
- The role of increased temperature on immunity and homeostasis in cold-blooded vertebrates is an understudied yet important field. This work not only examines how immunity is impacted by fever, but also incorporates an infection model and examines resolution of the response. This work can serve as a model for other groups interested in the study of hyperthermia and immunity.
Thank you very much.
- Generally speaking, I agree with the authors' strategy and interpretations of the data.
- In the Introduction, the authors chose to begin with how fever in endotherms impact the immune system. Considering that this work exclusively examines the response of a teleost (goldfish), the authors might consider flipping the way they present this work. After all, cold-blooded vertebrates rely on this response because of their basic physiology.
We chose to begin with a description of fever in endotherms because we know less about those immune mechanisms impacted by fever in ectotherms. The goal was to provide points of comparison based on published datasets. Indeed, we also expect differences between cold- and warm-blooded vertebrates based on their basic physiologies. However, it is interesting that despite different physiologies and thermoregulatory strategies, common biochemical pathways appear to regulate fever across cold- and warm-blooded vertebrates. This is now captured more clearly in the Introduction section (lines 134-136). Added support also comes from the work that we present in this study, including fever inhibition experiments using ketorolac tromethamine (lines 244-253; Figure 3C).
- I thought the set up of the work in figure 1 was innovative and could provide an example of how to study such a problem.
Thank you. Very much appreciated.
- Figure 2 was (to me) unexpected. One would not expect such tight response to hyperthermia and infection. This experiment in and of itself was quite interesting, and worth following up in future experiments (by the authors and other groups).
The level of homogeneity in the behavioural responses shown in Figure 2 was a big part of why we pursued this work. It was striking that fish would display such consistency in behaviour during the febrile window, regardless of whether they were evaluated in groups or individually. To us, this suggested that the temperature chosen and the kinetics of this thermal preference are central for modulation of downstream biological processes. Added support for the importance of precise thermal selection comes from "failed" experiments during this study where incoming aquatic facility water temperatures fluctuated due to factors outside of our control. This caused temporary disruption to the temperatures available to these fish in the annular thermal preference tank. In these cases, we noted disruption of both classical behaviours shown in Figure 2 as well as downstream benefits.
- The other work, on the response to infection and the resolution of infection were unique to this paper, and (sorry to be repetitive) can be an example of how to devise such studies.
Thank you.
- On the other hand, I am not sure this is a study of "fever." That implies how increased temperature impacts immunity and resolution in endotherms. Perhaps the authors could temper the comparisons between cold- and warm-blooded vertebrates regarding the response to hyperthermia.
We believe that for those mechanisms that are evolutionarily conserved, the teleost system will offer an opportunity for novel insights into the effects of fever induction and disruption. Indeed, this animal model offers multiple advantages. But we agree that much work remains to establish the extent of this conservation and now highlight this issue more clearly (lines 454-455).
An additional note on hyperthermia versus fever: although both terms are sometimes used interchangeably in the literature, we make a distinction between them. Hyperthermia captures an increase in core body temperature. However, this alone is not sufficient to engage the CNS (representative results shown in Figure 3-figure supplement 1). Consistent with prior descriptions of fever (e.g. Nat Rev Immunol (2015)15:335-49; Arch Intern Med (1998)158:1870-81), we also show that our model results in CNS engagement (Figure 3A), induces systemic pyrogen release (Figure 3B), triggers classical sickness behaviours (Figure 2), and promotes immune function (Figures 4-7).
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eLife assessment
This study addressed a long-standing question in biology - the role of fever during infections. Using innovative research strategy, the authors provide compelling evidence for the positive impact of higher body temperature on both pathogen clearance and tissue repair. This study thus provides important advances in our understanding of host defense and its connection with physiology and behavior.
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Reviewer #1 (Public Review):
The role of increased temperature on immunity and homeostasis in cold-blooded vertebrates is an understudied yet important field. This work not only examines how immunity is impacted by fever, but also incorporates an infection model and examines resolution of the response. This work can serve as a model for other groups interested in the study of hyperthermia and immunity.
Generally speaking, I agree with the authors' strategy and interpretations of the data.
- In the Introduction, the authors chose to begin with how fever in endotherms impact the immune system. Considering that this work exclusively examines the response of a teleost (goldfish), the authors might consider flipping the way they present this work. After all, cold-blooded vertebrates rely on this response because of their basic physiology.
- …
Reviewer #1 (Public Review):
The role of increased temperature on immunity and homeostasis in cold-blooded vertebrates is an understudied yet important field. This work not only examines how immunity is impacted by fever, but also incorporates an infection model and examines resolution of the response. This work can serve as a model for other groups interested in the study of hyperthermia and immunity.
Generally speaking, I agree with the authors' strategy and interpretations of the data.
- In the Introduction, the authors chose to begin with how fever in endotherms impact the immune system. Considering that this work exclusively examines the response of a teleost (goldfish), the authors might consider flipping the way they present this work. After all, cold-blooded vertebrates rely on this response because of their basic physiology.
- I thought the set up of the work in figure 1 was innovative and could provide an example of how to study such a problem.
- Figure 2 was (to me) unexpected. One would not expect such tight response to hyperthermia and infection. This experiment in and of itself was quite interesting, and worth following up in future experiments (by the authors and other groups).
- The other work, on the response to infection and the resolution of infection were unique to this paper, and (sorry to be repetitive) can be an example of how to devise such studies.
- On the other hand, I am not sure this is a study of "fever." That implies how increased temperature impacts immunity and resolution in endotherms. Perhaps the authors could temper the comparisons between cold- and warm-blooded vertebrates regarding the response to hyperthermia.
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Reviewer #2 (Public Review):
Fever is an ancient and conserve response to infection from invertebrates to humans. However, the functional benefits of engaging fever responses are not clear, especially when it comes to moderate fever responses where pathogen growth Is not impaired by temperature. This study aims to develop a natural in vivo fever model in fish that overcomes many of the technical challenges to investigate fever in mammals. In ectotherms, fever is manifested as a behavioral response by which animals move to warmer temperatures. By using this new developed in vivo behavioral ring, the present study reveals new functional roles for fever in vertebrates. Additionally, upon infection, sickness behavior did not only consist of fever, but two novel lethargic behaviors not previously described in fish. The experimental evidence …
Reviewer #2 (Public Review):
Fever is an ancient and conserve response to infection from invertebrates to humans. However, the functional benefits of engaging fever responses are not clear, especially when it comes to moderate fever responses where pathogen growth Is not impaired by temperature. This study aims to develop a natural in vivo fever model in fish that overcomes many of the technical challenges to investigate fever in mammals. In ectotherms, fever is manifested as a behavioral response by which animals move to warmer temperatures. By using this new developed in vivo behavioral ring, the present study reveals new functional roles for fever in vertebrates. Additionally, upon infection, sickness behavior did not only consist of fever, but two novel lethargic behaviors not previously described in fish. The experimental evidence is compelling and supports the authors' conclusions. The data presented strongly indicates that moderate fever levels are critical for fine tuning immune responses to pathogens. By triggering earlier but weaker antimicrobial defenses, moderate fever in teleosts results in controlled inflammation and improved wound healing. These exciting results reveal novel roles of fever as a way to minimize the collateral damage that inflammatory responses often cause to the host. This work advances our conceptual view of the evolutionary advantages that fever brings to host-pathogen interactions. The technological development of the annular temperature preference tank can now become the gold standard platform to investigate the consequences of fever during teleost infection.
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