Fever, Immunity, and Molecular Adaptations

Abstract

The heat shock response (HSR) is an ancient and highly conserved process that is essential for coping with environmental stresses, including extremes of temperature. Fever is a more recently evolved response, during which organisms temporarily subject themselves to thermal stress in the face of infections. We review the phylogenetically conserved mechanisms that regulate fever and discuss the effects that febrile-range temperatures have on multiple biological processes involved in host defense and cell death and survival, including the HSR and its implications for patients with severe sepsis, trauma, and other acute systemic inflammatory states. Heat shock factor-1, a heat-induced transcriptional enhancer is not only the central regulator of the HSR but also regulates expression of pivotal cytokines and early response genes. Febrile-range temperatures exert additional immunomodulatory effects by activating mitogen-activated protein kinase cascades and accelerating apoptosis in some cell types. This results in accelerated pathogen clearance, but increased collateral tissue injury, thus the net effect of exposure to febrile range temperature depends in part on the site and nature of the pathologic process and the specific treatment provided.

Fever and sickness behavior: Friend or foe?

“…From these observations it was concluded that a fever-like response must have developed 600 million years ago, before the appearance of adaptive immunity but in the setting of established and well-conserved heat shock and innate immune responses (Hasday et al 2014). This evolutionary aspect of fever was frequently used as support for an adaptive value of fever with special emphasis on the fact that such an energetically expensive process has persisted in many groups of organisms for millions of years (Kluger et al 1996).…”

“…The use of behavior to increase body temperature (Tb) has been observed in infected invertebrates including arthropods, annelids and poikilothermic vertebrates (Hasday et al 2014). From these observations it was concluded that a fever-like response must have developed 600 million years ago, before the appearance of adaptive immunity but in the setting of established and well-conserved heat shock and innate immune responses (Hasday et al 2014).…”

“…It should thus be kept in mind that treating fever either with physical or pharmacological means will always interfere with the tightly orchestrated process of inflammation. Suppressing fever by physical cooling will attenuate most components of innate immunity as febrile temperature aides these processes (Hasday et al 2014). The use of pharmacological tools with antipyretic properties will reduce or even eliminate mediators, which may be required for the host defense process (Zhang and Rivest 2001).…”

Cerebral Vascular Control and Metabolism in Heat Stress

“…Although on a continuum, mild, moderate, and severe heat stress is defined as a core temperature increase of ≤1.0, 1.0 to 1.5, and ≥1.5 • C, respectively. We do not provide an overview of increased temperature associated with fever as this encompasses a nearly distinct pathological state from passive (external heating) or exertional (exercise induced) etiologies, for reviews, see (192,385). Exertional and passive heat stress, or a combination of the two (strictly described later in: Quantifying heat illness and heat stroke), although separate in etiology, is not uniquely covered in this review.…”

Controversies in the temperature management of critically ill patients

“…Textbooks on physiology document that in fever, exogenous and endogenous pyrogens actively shift the thermoregulatory threshold temperature upwards by affecting the thermoregulatory center control. Fever-like responses, including behavioral thermoregulation, are observed in invertebrates having solely innate immune responses, and are speculated to have developed 600 million years ago [43]. Thus, fever acts as a defensive reaction against pyrogens and foreign objects by increasing their clearance, the immune response, and heat-shocking proteins, along with protection against infectious agents [44][45][46].…”