Conserved Fever Pathways across Vertebrates: A Herpesvirus Expressed Decoy TNF-α Receptor Delays Behavioral Fever in Fish

摘要

class="head no_bottom_margin" id="sec1title">IntroductionWhen infected by pathogens, endotherms and ectotherms can both increase their body temperature to limit the infection. In endotherms, this cardinal response to infection is called fever (for a recent review, see ). It relies mainly on thermogenesis, and also on physiological and behavioral modifications leading to reduced heat loss by the body. With the exception of a few rare examples, ectotherms lack intrinsic thermogenesis and so have a body temperature very close to the temperature of the environment. In a temperature gradient, ectotherms select a species-specific range of preferred temperature, which is defined as final thermal preferendum (FTP) (for a recent review, see ). In response to infection or injection of exogenous pyrogens, ectotherms can increase their body temperature above their FTP through migration to warmer environments. This phenomenon is known as behavioral fever and is defined as an acute increase of the FTP consecutive to an infection (). Behavioral fever has been reported in a broad range of ectotherms including vertebrates (fishes, amphibians, and reptiles) and invertebrates.Regulation of behavioral fever in ectotherms is evolutionarily related to fever in endotherms at various levels of the relevant regulatory pathways (, ), including the roles of exogenous pyrogens as inducers, the importance of the hypothalamic preoptic area as an integration site for pyrogenic signals, and the key role of prostaglandins as effector mediators. However, no study has yet determined whether this evolutionary relationship extends to the endogenous pyrogens, namely the cytokine mediators that inform the brain of exogenous pyrogens detected by immune cells throughout the body. In endotherms, cytokines such as interleukin 1β (IL-1β), IL6, tumor necrosis factor α (TNF-α), and interferons (, ) have been shown to act as endogenous pyrogens.At least in some infectious models, fever in endotherms and behavioral fever in ectotherms can increase host survival (, ). This beneficial effect is the consequence of the elevation of body temperature, which enhances the efficiency of both innate and (when existing) adaptive immune mechanisms and can restrict replication of invading pathogens. Through the expression of dedicated genes, pathogens are able to manipulate virtually all the physiological processes of their host that can affect their replication and transmission. However, to date, there is no report of a pathogen being able to affect the expression of behavioral fever by its host.Cyprinid herpesvirus 3 (CyHV-3) is the causative agent of a lethal, highly contagious and notifiable disease in common and koi carp (Cyprinus carpio) (). The outcome of CyHV-3 infection is highly dependent on temperature both in vitro and in vivo, with temperatures between 18°C and 28°C allowing viral replication in vitro and development of CyHV-3 disease in vivo, whereas temperatures above 30°C rapidly block CyHV-3 replication and the development of CyHV-3 disease (). During our studies of CyHV-3 pathogenesis (), we observed that carp infected at 24°C (within the FPT of healthy carp) tended to concentrate around the tank heater when it was running. This observation led us to hypothesize that infected subjects might express behavioral fever in natural environments where temperature gradients exist ().Here, we used the infection of carp by CyHV-3 as a homologous virus-host model to study the expression of behavioral fever. We demonstrate the ability of this virus to alter this behavior of its host through the expression of a single gene and identify the role of TNF-α as a mediator of behavioral fever in ectotherms.