Fever — an enemy to bring down or an ally of the body?

Aim of the study: Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection.

Results: The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. In this Review, we discuss our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. We also discuss the emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function.

Aim of the study: Fever during influenza A virus (IAV) infection is triggered by the innate immune response. Various factors contribute to this response, including IAV mini viral RNAs (mvRNA), which trigger RIG-I signaling when their replication and transcription are dysregulated by template loops (t-loops).

Results: Here, we show that IAV infection at temperatures that simulate fever leads to increased antiviral signaling in H1N1 and H3N2 infections. Mathematical modeling and experimental analyses reveal that differential IAV nucleoprotein and RNA polymerase production increase mvRNA and interferon production. Moreover, at the higher infection temperature, mvRNAs with dysregulating t-loops contribute most to the innate immune activation. We propose that fever during IAV infection can establish a positive feedback loop in which elevated aberrant RNA synthesis and innate immune activation can contribute to the dysregulation of cytokine production.

Aim of the study: Fever's ability to manipulate the character and extent of physiological temperature gradients correlates with the unusual influence different physiological temperatures have upon model immune responses in vitro. This relationship may help to explain the remarkable evolutionary conservation of the febrile response to infection.

Results: The differential sensitivity of these processes to different physiological temperatures suggests that fever's biological purpose with respect to the immune system is the elimination of lower peripheral tissue temperatures rather than the elevation of core temperatures. However, further studies may reveal that some functions are amplified by the core temperature transitions while other functions are selectively regulated by peripheral tissue temperature transitions. The critical cell for the temperature dependence of immune responses seems to be the Th since its ability to produce cytokines is highly temperature dependent. In contrast, macrophages produce cytokines equally well at all temperatures except those of the febrile core, a feature which may serve to downregulate the production of endogenous pyrogens.

Aim of the study: Fevers are an ancient feature of the inflammatory microenvironment. While fevers may improve the immune response to pathogens, mechanisms are unclear.

Results: Recent evidence indicates that metabolic programs initiated by fever are maintained upon return to thermo-normality, potentially providing a lasting benefit. Despite its impact, temperature remains overlooked and warrants further study. This is especially apparent when considering the wide temperature differential between tissues within the body and during inflammatory disease progression. We propose that differences in the metabolic and stress responses between T cell subsets upon thermal stress contribute to determining immune cell makeup and fate during inflammation.

Aim of the study: The development and function of the immune system is regulated by neuroendocrine factors. Immune function may be divided into adaptive and natural immunity.

Results: Bone marrow activity and leukocyte function are high and the liver is converted to the rapid production of acute-phase proteins (APP). APP include LBP, CRP, fibrinogen, some complement components, enzyme inhibitors, and anti-inflammatory proteins, which may rise in the serum from several hundred to a thousand times within 24-48 hr. Therefore, natural immunity is a polyspecific response to homotopes, which functions as an instantaneous defense mechanism in health and which is rapidly boosted by cytokines and hormones during febrile illness. This is a highly successful defense reaction, as in the overwhelming majority of cases, febrile illness leads to recovery and the development of adaptive immunity in man and higher animals.

Aim of the study: Fever is one of the human body's most effective strategies in fighting infections. However, its precise role in eliminating pathogens, specifically the influence of heat on the bacterial cells on the mechanistic level under febrile temperatures has never been fully delineated.

Results: The concept of fever, as the immune system's first line of defense against pathogens involves two main components: the inflammatory response and the heat, which stimulates the host's immune cells and affects pathogens. This article summarizes independent findings, grouping the development of fever into a circular model, starting with pathogen invasion and the release of bacteria's exogenous pyrogens, continuing through the host immune response, and debating on the impact of fever on numerous human pathogens. This model focuses broadly on processes occurring within bacteria, particularly pathogen adaptation and the detrimental effect of heat released during fever on pathogen death. We also discussed the impact of commonly used antipyretics, such as acetaminophen, ibuprofen, and aspirin, on the overall outcome of infection and provided a framework within which new concepts and findings in this field can be developed.