Behavioural fever is a synergic signal amplifying the innate immune response

Abstract

Behavioural fever, defined as an acute change in thermal preference driven by pathogen recognition, has been reported in a variety of invertebrates and ectothermic vertebrates. It has been suggested, but so far not confirmed, that such changes in thermal regime favour the immune response and thus promote survival. Here, we show that zebrafish display behavioural fever that acts to promote extensive and highly specific temperature-dependent changes in the brain transcriptome. The observed coupling of the immune response to fever acts at the gene–environment level to promote a robust, highly specific time-dependent anti-viral response that, under viral infection, increases survival. Fish that are not offered a choice of temperatures and that therefore cannot express behavioural fever show decreased survival under viral challenge. This phenomenon provides an underlying explanation for the varied functional responses observed during systemic fever. Given the effects of behavioural fever on survival and the fact that it exists across considerable phylogenetic space, such immunity–environment interactions are likely to be under strong positive selection.

Behavioral fever in ectothermic vertebrates

“…Moreover, increased level of plasma PGE 2 was correlated with the induction of behavioral fever in dsRNA-challenged zebrafish (Boltaña et al, 2013). These data, together with studies using COX inhibitors strongly indicate that synthesis of PG seems to be necessary for the expression of behavioral fever in ectothermic vertebrates (Fig.…”

“…Grans et al (2012) demonstrated significantly higher IL1b expression in head kidney of rainbow trout (Oncorhynchus mykiss) injected with LPS and subjected to simulated behavioral fever by increasing water temperature of 2.5 C (up to 16.0 C) after injection, as compared to fish that were injected with LPS and kept in constant water temperature of 13.5 C (Grans et al, 2012). The study of Boltaña et al (2013) suggested that behavioral fever induced by injection of zebrafish with synthetic dsRNA (poly I:C) and demonstrated by shift in thermal preference from 29.4 C to 33.1 C, promotes the emergence of a highly specific anti-viral immune response by induction of the transcription of specific genes in brains of zebrafish (Boltaña et al, 2013). This is in accordance with previous observations that higher temperature has a positive effect on viral clearance in fish (Avunje et al, 2012;Novoa et al, 2010).…”

“…Up to date, behavioral fever has been described in all groups of ectothermic vertebrates including reptiles (Bernheim and Kluger, 1976a,b;Burns et al, 1996;do Amaral et al, 2002;Hallman et al, 1990;Kluger et al, 1975;Merchant et al, 2007Merchant et al, , 2008Monagas and Gatten, 1983;Muchlinski et al, 1995;Ortega et al, 1991;Ramos et al, 1993;Vaughn et al, 1974), amphibians (Casterlin and Reynolds, 1977;Kluger, 1977;Murphy et al, 2011;Myhre et al, 1977;Richards-Zawacki, 2010;Sherman et al, 1991), fish (Boltaña et al, 2013;Cabanac and Laberge, 1998;Covert and Reynolds, 1977;Grans et al, 2012;Reynolds, 1977;Reynolds et al, 1976Reynolds et al, , 1978 but also in invertebrates (Campbell et al, 2010;Elliot et al, 2002) and newborn mammals, which in response to bacterial pyrogens are unable to develop fever physiologically but do so behaviorally (Satinoff et al, 1976). However, there have been some contrasting data showing that injection of pyrogens, killed bacteria or parasites in some species of lizards (Don et al, 1994;Hallman et al, 1990;Laburn et al, 1981;Muchlinski et al, 1995;Ortega et al, 1991;Schall, 1990), turtles (Zurovsky et al, 1987b), snakes (Burns et al, 1996;Zurovsky et al, 1987a) and fish …”

“…1b) including LPS (Cabanac and Laberge, 1998;do Amaral et al, 2002;Grans et al, 2012;Merchant et al, 2007Merchant et al, , 2008Reynolds et al, 1978;Sherman et al, 1991), various species of Gram-positive and Gram-negative bacteria, administrated as killed or live forms (Bernheim and Kluger, 1976a,b;Burns et al, 1996;Casterlin and Reynolds, 1977;Covert and Reynolds, 1977;Hallman et al, 1990;Kluger, 1977;Kluger et al, 1975;Monagas and Gatten, 1983;Muchlinski et al, 1995;Myhre et al, 1977;Ortega et al, 1991;Ramos et al, 1993;Reynolds, 1977;Reynolds et al, 1976Reynolds et al, , 1978Vaughn et al, 1974), fungi (Murphy et al, 2011;Richards-Zawacki, 2010), ectoparasite (Gyrodactylus turnbulli) (Mohammed et al, 2016), synthetic dsRNA (poly I:C) (Boltaña et al, 2013) or viruses (Boltaña et al, 2013). Because of the relatively low sensitivity of fish and toads to LPS, the dose used to induce behavioral fever in these animals (toad:…”

“…Prevention of behavioral fever development during bacterial infection with A. hydrophila in lizards Dipsosaurus dorsalis, by physical (Kluger et al, 1975) or pharmacological means (injection of sodium salicylate) (Bernheim and Kluger, 1976a), as well as in fish Carassius auratus by physical means (Covert and Reynolds, 1977), was harmful to infected animals and resulted in higher mortality as compared to individuals which were allowed to express behavioral fever. Recently, Boltaña et al (2013) demonstrated that zebrafish (Danio rerio) infected with spring viremia of carp virus (SVCV) and allowed to express behavioral fever, rapidly combat viral infection, do not develop clinical symptoms of infection and clear replicating virus from the body, in contrast to zebrafish held under constant conditions (Boltaña et al, 2013).…”