Opinion
Temperature stress and parasitism of endothermic hosts under climate change Neil J. Morley and John W. Lewis School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey, TW20 0EX, UK
Climate change is a major threat to global environmental stability and is predicted to cause more frequent extreme weather events with higher levels of heat and cold stress. The physiological effects of such events on parasitic infections within endotherms are poorly studied and rarely considered in the context of climate change where an emphasis on ectothermic components of parasite life cycles (free-living stages and invertebrate hosts or vectors) predominates. However, thermal stress can affect parasite establishment, growth, fecundity, and development within endothermic hosts and may thus potentially influence transmission potential. Such changes can be caused by temperature effects on host physiological homeostasis, predominantly endocrine and immune systems, and may have wide implications for parasite epidemiology under extreme climatic events. Parasitism of endotherms under a changing climate Climate change is one of the greatest threats to global environmental and economic stability, predicted to cause widespread changes in temperature and precipitation with an increased frequency of severe weather conditions [1]. The most recent IPCC (Intergovernmental Panel on Climate Change) assessment [1] considers that there will be more frequent hot and fewer cold temperature extremes on a daily and seasonal basis. Heat waves are very likely to occur with a higher frequency and duration, although occasional cold winter extremes will continue to arise. Temperature effects on animals are therefore one of the primary variables of scientific concern, either through rises in average temperature conditions or by sudden thermal changes associated with an extreme climatic event (see Glossary) such as heat waves, droughts, and cold snaps. For parasites, attention has focused on important modifications to free-living stage viability and interactions with ectothermic hosts or vectors [2], especially associated with Corresponding author: Morley, N.J. ([email protected]). Keywords: climate change; endotherms; parasites; physiology; endocrinology; immunology. 1471-4922/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2014.01.007
changes in geographical distribution of insect vectors such as mosquitoes [3]. There is no doubt that this focus is a research priority; nevertheless, an emphasis almost exclusively on ectothermic components ignores the direct effects of temperature on endothermic hosts within the life cycles of parasites. In particular, cold and heat stress which accompany changes in temperature under extreme climatic events may induce trauma that can influence physiological and endocrinological homeostasis of endotherms (Box 1). An increased frequency of such events is one of the most detrimental yet understudied aspects of climate change on endotherms [4,5], yet seldom considered in parasitology [6]. These often short but extreme temperature shifts impose different demands on endotherms than a slowly warming climate [4], and during the past decade may be associated with increased reports of mass die-offs [7]. Such changes in the physiological homeostasis of endotherms may seriously affect their suitability as hosts. Under laboratory conditions, stress is known to influence the occurrence and virulence of a range of infectious diseases in endothermic hosts [8]. In particular, the physiological dynamics of many protozoan and metazoan parasitic infections have been negatively or positively affected by temperature stress, although this has rarely been considered at the population level despite the implications for parasite epidemiology. Nevertheless, there are a diverse range of stress effects at the levels of individual host or
Glossary Ectotherm: an animal that is dependent on the external environment to maintain its body temperature. Endotherm: an animal that generates heat to maintain its body temperature independent of, and typically above, its environment. Extreme climatic events: these are events at the boundaries of the range of weather experienced in the past and can include severe episodes such as heat waves, droughts, intense rainfall, or cold snaps. Heterothermy: endotherms that can switch between an ectothermic or endothermic physiological state dependent on life history requirements, typically found in animals that hibernate in response to external conditions. Homeothermy: animals that maintain a stable body temperature regardless of external environmental conditions. Physiological homeostasis: the ability of an animal to maintain a stable internal environment by physiological processes. Thermoneutral zone (TNZ): this represents the optimal range of environmental temperatures for an endotherm, where the basal rate of heat production is in equilibrium with the rate of heat loss to the external environment and the organism does not have to use large amounts of energy to control its body temperature. Trends in Parasitology, May 2014, Vol. 30, No. 5
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Box 1. Effects of temperature stress on endotherms With the exception of migratory and hibernatory cues, direct thermal impacts of climate change are rarely described for endotherms [4]. However, laboratory studies have determined that endothermic metabolic rates are substantially higher than those of ectotherms and metabolic heat production, which is regulated in response to environmental temperature fluctuations, constitutes much of the energy expended by endotherms when environmental temperatures deviate from the TNZ. Therefore, thermal variations associated with climate change are likely to strongly influence endotherms and this may be fundamentally different from effects on ectotherms [4]. Depending on the thermoregulatory characteristics of individuals, populations, or species, energy expenditure, which maintains a constant body temperature, may rise as ambient temperature increasingly diverges from the TNZ of endotherms, thereby lessening the energy available for other fundamental biological functions [4]. In cold environments, homeothermic endotherms change the extent of thermal insulation (fur or feathers) and peripheral blood flow with increased food consumption as neuroendocrine receptors respond to changing thermal conditions. Elevated levels of adrenocortical hormones are produced, and there is greater activity of the pituitary and thyroid glands. Increased endocrine activity creates immunosuppressive and anti-inflammatory effects, thus suppressing many aspects of the immune system. Although endotherms become less active, they maintain an elevated level of heat production, accompanied by changes in the enzyme activities of muscles, liver, and other organs. Prolonged cold exposure can lead to the enlargement of more active organs such as the heart, intestine, liver, kidney, and thyroid and adrenal glands [63–65].
population which can result in complex interactions between stress and disease [9]. However, physiological mechanisms and thermal biology theory remain poorly integrated into climate change–disease studies [10]. Indeed, there has been a tendency to ignore endotherm physiological responses to climate change and to consider fluctuations in levels of infections a product of the effects on ectothermic components of their life cycles alone. However, both endothermic hosts and their parasites function optimally within certain physiological temperature ranges, the thermoneutral zone (TNZ), and perform gradually more poorly the further the thermal environment deviates from these conditions. Most host–parasite interactions are mediated by physiological responses which, in turn, can be influenced by environmental conditions such as climate. Therefore, only by understanding endotherm physiology in combination with ectothermic aspects of host–parasite relationships will a robust mechanistic understanding of how climate change affects parasitic infections in host populations be attained [10]. In this review, we present evidence from laboratory studies of the direct effects of cold and heat stress on parasites within endothermic hosts. In these conditions, animals are normally maintained in stable ambient environments at temperatures typically ranging from 228C to 258C and exposed to experimental high or low temperatures that constitute thermal stress. In natural environments, animals will be found in habitats with a range of different ambient temperature conditions. Consequently, thermal stress may occur at different temperatures from those found under laboratory conditions. However, the types of physiological responses of endotherms to thermal stress remain constant and therefore the effects on parasite viability found in laboratory studies will be reflected in the natural environment. Under a changing climate, where 222
The ability of some heterothermic endotherms to enter hibernation during extended cold periods may place them at a competitive advantage over homeothermic ones [4]. Heterotherms lower their body temperature, decreasing the level of metabolism and other aspects of functional biology required for a given degree of thermal insulation. Nevertheless, periodic arousal from hibernation is required to activate a dormant immune system for combating any infectious agents [66]. The associated marked energetic costs may in part reflect a trade-off between maintaining a long-term energy balance as well as contending with parasitic infections. Nevertheless, different species of heterotherms, whose populations may thermoregulate independently to similar changes in climate, exhibit diverse levels of metabolic rates and energy expenditure during hibernation [4], which may influence their immunocompetence. By contrast, endotherms exposed to a hot environment decrease their metabolism, oxygen uptake, and food consumption due to the responses of neuroendocrine mechanisms to changing thermal conditions. The lowered food intake, in turn, influences thyroid activity, leading to a reduction in associated hormonal levels. The production of testosterone is also inhibited, whereas plasma corticoids initially increase and then decrease following prolonged exposure. Such reduced endocrine activity appears to benefit many aspects of the immune system, allowing optimal responses to challenges. There is a decline in weight of a number of internal organs and a reduction in oxidative enzyme activity, particularly in the liver. The level of dermal blood flow is adjusted to increase heat loss, largely at the expense of circulation to other regions of the body [56,64,65].
the frequency of extreme high temperatures may increase whilst those of cold temperature extremes decrease, we consider that overlooking these thermal stress effects at the individual level may undermine attempts to create predictive frameworks of the influence of climate change on host–parasite dynamics at the population level. Cold extremes Under the stress caused by experimental cold (4–108C air temperature) exposure of infected endotherms, changes to parasite viability can be separated into two groups dependent on whether the host is hibernatory (heterothermic) or non-hibernatory (homeothermic). In homeothermic hosts (mice, rats, canaries), protozoan infections demonstrate a general trend of increased parasitemia with corresponding rises in host pathology and mortality [11–14], although other factors such as social status can moderate hormone and immune responses, influencing parasite levels at these temperatures [15]. Furthermore, a more complex pattern of responses associated with host and parasite strains emerges from studies with trypanosomes [11,16–18] (Box 2). For helminths, experimental cold stress induces a greater range of effects in homeothermic hosts (mice and gerbils). Many tapeworm species, including both adult and metacestode stages, show patterns of higher prevalences more prominently in male mice [19–22]. By contrast, some metacestode species demonstrate lower parasite intensity and growth [23] or remained unaffected [24]. Differences between individual strains of hosts are also apparent, as in the case of the nematode Trichinella spiralis, which demonstrates reduced adult intensity in the intestine of one mouse strain but remains unaffected in another [25]. By contrast, both Schistosoma japonicum and Schistosomatium douthitti show neither differences
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Box 2. Trypanosomes: a case study Trypanosomes are kinetoplastid eukaryote parasites of vertebrates, mainly transmitted by blood-feeding invertebrates, and are likely to increase in incidence or expand their geographical range under climate change [67]. Most species live in the blood and tissue fluids of endothermic hosts and the effects of temperature stress on these parasites have been extensively studied in the laboratory. In cold environments (108C) the parasite load of Trypanosoma cruzi-infected rodents generally increases along with a corresponding rise in host mortality rates [11,68]. Exposure to 48C for 4 h also increases parasitemia, but host survival rates are not substantially altered [69]. Furthermore, ‘non-pathogenic’ species such as Trypanosoma duttoni become virulent in rodents when exposed to these temperature regimes and a low food supply [70]. Nevertheless, such responses are not consistent across all studies, probably associated with host/parasite species-specific and strain-specific variations. For example, unlike T. cruzi exposure of mice infected with Trypanosoma evansi or Trypanosoma brucei to 48C results in a variable reduction in parasite load, but a comparable host survival rate with mice maintained at 22–268C [16,17]. Similarly, two strains of mice show different levels of infections with Trypanosoma musculi at 108C, either reducing parasitemia or remaining largely unchanged [18]. Trypanosome-infected rodents maintained at high ambient laboratory temperatures (358C) over a number of months show reduced parasite loads, cardiac and skeletal muscle pathology, and lowered host mortality rates [11,16,68,71]. Rodents already showing high
in parasite intensity nor infection success compared with mice maintained at room temperature [26,27]. Nevertheless, S. japonicum demonstrates delayed fecundity, suggesting that growth and development are slower under these conditions [28]. Under natural environments of winter cold extremes, there have been only limited studies on parasite viability in homeotherms. Nevertheless, it is apparent that these conditions influence host immune response which, in turn, changes helminth occurrence [28–30]. In heterothermic animals, experimental cold stress during periods of hibernation may affect parasites directly due to the drop in body temperature and indirectly through changes to physiological homeostasis of the host. Studies on Toxoplasma gondii infections in squirrels found that hibernation prolonged the survival of infected hosts because it appeared that the lowered body temperature of the hosts inhibited multiplication of the parasite [31]. However, Entamoeba infections demonstrate more variable responses in the intestine of hibernating squirrels with an increase in parasitemia [32] or a complete loss of infection [33] during this temperature exposure. Helminths also demonstrate variable responses in heterothermic hosts. T. spiralis is uniformly negatively affected in many hibernatory species (dormice, hamsters, bats) with nematode development either reduced or completely prevented during the host’s phase of torpidity. The intensity of infection is also lower in hosts induced into hibernation within 2 days of experimental infection compared with those induced 15 days later [34–36]. By contrast, prolonged hibernation of ground squirrels results in the loss of most infections with Nippostrongylus brasiliensis, whether induced immediately following experimental infection or in hosts with well-established adult worms [37]. The intestinal cestode Hymenoplepis citelli also shows reduced growth and development in ground squirrels
parasitemia at room temperatures rapidly become aparasitemic after transfer to 358C [16,71], and when parasite numbers decline to undetectable levels and the hosts return to room temperature, no relapse of parasitemia or mortality rates are detected [71]. Nevertheless, other studies have found that heat stress has little effect on parasite levels [72]. The number of parasites harbored in a host at these high temperatures can vary substantially between different rodent [18,62] and parasite strains [16] and, in particular, variations in parasite strains can cause effects ranging from almost no change in parasitemia to a rapid elimination of parasites resulting in ‘self cure’ [16,17,72]. This reduction in parasitemia appears to be associated with a change in the immunological response of the host as well as direct effects on the trypanosomes themselves. It is apparent that there is a significant optimization of both parasite-specific and nonspecific cellular and humoral immune responses [53,54,72], providing an elevated level of protection. Although changes in immune responses appear to be the main factor in determining parasitemia under laboratory conditions, high temperatures also appear to directly affect the parasites. This results in increased levels of morphological deformities and lowered reproduction, due to sensitivity to reduced oxygen uptake of hosts under these conditions [16,56]. However, it remains to be determined if these changes reported from laboratory studies are replicated under natural conditions found during extreme climatic events.
during hibernation [38], whereas certain trematode species seem to demonstrate more mixed responses, which are probably related to the stage of development when hibernation is induced and/or dependent on the strain of parasite and host. For example, Fasciola hepatica demonstrates reduced development and maturation if squirrel hibernation occurs before worms have migrated to the bile duct, whereas worms do not survive if hibernation is induced following establishment within the bile duct [39]. For schistosomes such as Schistosoma mansoni and S. douthitti, there are no differences in levels of infection in a range of hibernating host species (meadow jumping mouse, squirrels, hamsters) compared with room temperature controls, even if infections occurred before or after acclimation to low temperatures or over prolonged periods of hibernation. Schistosomes will also develop and produce viable eggs in hibernating hosts, although developmental rates are slower, with some adult worms surviving over a 58-day hibernation period without any apparent abnormalities [40] (D.W. Dery, PhD thesis, Florida State University, 1961). By contrast, the developmental rates of other strains of S. mansoni remain unchanged in hibernating hamsters compared with those maintained at room temperature [41] or may be rapidly immobilized in squirrels induced into hibernation, with adult worms accumulating in the liver where they are soon destroyed by leukocytes [42]. Studies under natural conditions also support the idea of a complex but generally negative effect of hibernation on helminths with a reduction in the occurrence of some species and a slower growth of others dependent on the hibernation habits of the host [43–45]. Heat extremes Infected endotherms under experimental heat stress (35–368C air temperature for mammals, 328C for birds) cause numerous changes in the viability of their parasites. In general, most protozoans studied are negatively affected 223
Opinion by such conditions with a reduction in parasitemia and pathology and an increase in host (mouse, hamsters) survival [11,46–47] (Box 2). High temperatures, at least in birds, need to be maintained for a minimum of 2 days for the viability of Eimeria species to be reduced [48], whereas in mice a lower temperature of 308C did not have a detrimental effect on the development of Leishmania braziliensis pifanoi (Z. Hayatee, PhD thesis, University of London, 1971). This suggests that both a minimum temperature and duration threshold need to be achieved before such negative effects become apparent. Differences in both parasite and host strains can influence the extent of any negative effects [16,17,47]. However, exceptions occur as in the case of T. gondii where an increase in pathology and a reactivation and spread of cysts was found in the brains of heat-stressed rats [14]. It is possible that these generally negative effects on parasites are not associated with a decline in their functional biology, particularly considering that Plasmodium berghi berghi has an increased synthesis of DNA in mice exposed to higher temperatures, indicating elevated multiplication and growth [49], thus suggesting that an improved host immune response may potentially be the primary variable. Helminths demonstrate a more complex response to these experimental temperature stresses. Mice acclimated to high temperature for 5 days became less susceptible to a subsequent percutaneous infection with the trematodes S. douthitti and S. mansoni [26,50]. However, a 10-day acclimation period did not significantly affect susceptibility to a subcutaneous infection with a different strain of S. mansoni. By contrast, mice infected subcutaneously at room temperature and then subjected to 358C or higher temperatures showed significantly lower intensities after only 1 day of heat stress and were found to be parasite-free after 6 weeks. Further studies showed that S. mansoni was only susceptible to such stresses during temperature exposures of 1–15 days post-infection but not from days 10 to 20, suggesting that the schistosomula, migratory larval stages that travel through the blood vessels to the liver, were most vulnerable to these conditions [51]. This narrow period of post-infection susceptibility may be a factor in the contradictory effects of heat stress on S. japonicum infections where levels of infections in mice remain unaffected, but by 7 weeks post-infection both male and female worms are shorter in length and the egg burden in host tissues was reduced compared with controls [27]. Cestodes such as hymenolepids are negatively affected by increased temperature, resulting in a reduction in growth, development, and egg production, which occurred more prominently in male mice [19,21]. Similarly, mice harbor lower burdens of Taenia crassiceps and Mesocestoides corti, and these tapeworms also show reduced growth, especially in male hosts [22,23]. By contrast, Echinococcus multilocularis had a higher growth rate and proliferation of cysts in gerbils at high temperatures [24]. Such a positive effect is also shown by the nematode T. spiralis in mice, with significantly higher numbers of adult worms, but this is dependent on the mouse strain [25]. Under natural conditions of heat extremes, it is difficult to disentangle thermal effects on free-living stages nor on ectothermic hosts or vectors from those derived directly in 224
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endothermic hosts. Nevertheless, the adult nematode Haemonchus contortus in sheep survived longer with higher fecal egg counts during an unusual summer of hot dry conditions [52], which may be associated with changes in host physiology. Further studies on parasite viability in endothermic hosts under natural heat extremes are therefore required to fully elucidate the range of potential effects. Effects of host physiological mechanisms on parasites It is generally considered that, because under most circumstances host body temperature does not substantially vary, changes in the levels of infections under experimental temperature stress are primarily due to thermal modifications in host physiology, particularly the endocrine and immune systems [19,20,25,37,53,54], although it remains to be determined if such results are replicated under natural conditions. Direct effects of environmental temperatures on parasites, however, cannot be completely ruled out, especially in heterothermic hosts under cold stress, but that we consider are likely to be secondary to indirect effects caused by changes in host physiological homeostasis (Box 1), radically changing conditions for parasites in a manner beyond those capable by thermal effects alone. Nevertheless, the exact physiological mechanisms influencing parasites under these conditions are poorly understood, but much can be inferred from known endocrinological and immunological changes in endotherm physiology (Box 1). These thermally induced changes can be placed in the context of known fluctuations in the host endocrine system that can either directly influence the functional biology of parasites, by facilitating infections and increasing growth and reproduction rates, or indirectly by altering the efficiency of the immune system [55] and thus altering the rate of parasite mortality. In particular, both adrenal hormones and sex steroids are potent immunomodulators, whose influence on the immune system are moderated by host sex and age [55]. Thus, the substantial changes that occur in the endocrine system under cold and heat stress (Box 1) can influence levels of parasitic infections. However, the exact physiological pathways that result in changes to parasitism remain difficult to determine because they will vary from one parasite species to another, dependent on the host organs and tissues they reside in or migrate through and the demands of the individual host–parasite relationship, which itself can be influenced by the intensity of infection. Nevertheless, although endocrine and immune changes appear to be the principal influence on parasites, other physiological variations may be of secondary importance. For example, lower levels of oxygen uptake under heat stress [56] may affect the viability of sensitive protozoan species, whereas increased or decreased food consumption and associated intestinal motility under cold or heat stress could influence growth and development of gut parasites [20]. It is apparent that the extent of temperature effects is highly dependent on the strain of parasite and host. In most cases, the above experiments were undertaken on laboratory strains that had been maintained for many years, and due to extensive inbreeding some caution must
Opinion therefore be taken when extrapolating data derived from these sources to the natural environment [57]. Similarly, conditions in which each experiment was undertaken are unlikely to be exactly the same from one study to another. However, regardless of the circumstances of individual experiments hosts were subjected to a level of temperature stress that deviated from long-term maintenance in ambient conditions, which closely reflected their TNZ. Nevertheless, from the limited evidence available, results obtained under laboratory conditions appear concordant at least with those obtained from natural sources under cold stress [43,44]. Potential implications for parasite transmission Temperature variations have a complex and relatively unappreciated effect on the course of parasitic infections within endothermic hosts at the individual level, but can such changes influence the epidemiology of parasites at the population level under extreme climatic events? Cold temperatures are regular seasonal features of mid- and highlatitude habitats. These conditions during winter can cause complex effects on parasite infections of homeotherms [30], even though transmission is interrupted in the absence of ectothermic hosts or vectors. At least some changes can be attributed to alterations in host immunity [58] and in turn with variations in the endocrine system. A reduction in the frequency of cold extremes may therefore change the physiological dynamics of host–parasite interactions over the winter, which may increase or decrease parasite occurrence within endothermic host populations. Such changes may be additionally impacted by an expanded seasonal transmission window through ectothermic components of parasite life cycles during milder temperature conditions in the spring and autumn. Nevertheless, alternative mechanisms influencing parasitism in endotherms need to be considered. For example, during harsh winters the availability of food for homeotherms may be reduced, which can have lethal consequences for animals [59]. Reduced food intake can also affect endotherm physiology, particularly immunity, changing their susceptibility to infections [60,61], but a reduction in the frequency of cold winter extremes under climate change [1] is likely to reduce the influence of such factors. Milder winters, associated with a decrease in the frequency of cold temperature extremes under climate change in mid- and high-latitude habitats [1], will also impact upon heterotherms by altering the pattern and duration of hibernation. Changes in the level of host thermoregulation, in turn, may reduce the effects on parasites within hibernatory animals, thereby changing the dynamics of the overwintering host–parasite relationship. Heat stress, associated with short-term extreme climatic events, may influence host endocrine and immune systems with consequent negative or positive effects on parasites. Under laboratory conditions, many parasites have lowered intensities/densities and reduced development and fecundity, although a smaller number of species or strains demonstrated the opposite. In addition, reduced feeding rates of endotherms at high environmental temperatures (Box 1) may lower the risk of infection from trophic-transmitted parasites. Under natural conditions,
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any change in the prevalence and intensity/density of parasites may, in the short-term, change both the health and alter transmission within host populations. An increased frequency of extreme climatic events and temperature stress could result in a persistent strain on parasite populations, potentially increasing the likelihood of long-term changes in levels of infection, particularly when combined with the impact such events are likely to have on ectothermic hosts or vectors. Nevertheless, wide variations in the effects of temperature stress associated with the type and strains of parasites or hosts exist, which must also be considered in the context of the many potential pathways that fluctuations in the endocrine and immune systems of the hosts may influence parasites. Such pathways will vary according to species, location within the host, and the nutritional demands and pathological effects the parasite induces in the host. Such complex physiological interactions between host and parasite under temperature stress suggest that the thermal impact associated with extreme climatic events may be patchy on a regional or local scale. Concluding remarks Optimal physiological temperature ranges (TNZ) exist for both endothermic hosts and their parasites. As environmental temperature conditions deviate from the TNZ, both organisms begin to function less well. Thus, extreme climatic events resulting in temperature stress have the potential to significantly influence levels of parasitic infections in endotherms. Under laboratory conditions, extreme environmental temperatures alter the physiology of endothermic hosts, thereby either benefiting or hindering parasite survival, development, or fecundity. Nevertheless, stress induced by temperature causes a complex series of changes in host–parasite relationships dependent on a range of factors including duration and timing of exposure in relation to parasite development, the particular strain of parasite or host, the site of infection within the host, and the thermoregulatory characteristics of individual host species. However, the role of host acclimation to temperature extremes and its influence on parasite viability still remains to be fully elucidated [9]. Acclimation appears to have little influence under some conditions but can play a pivotal role in other conditions [26,27,50,62]. Greater consistency in experimental design of future laboratory studies may provide more obvious patterns in responses of parasites to thermal stress in endothermic hosts becoming apparent. Under natural conditions, physiological changes of the endotherm host during extreme climatic events may affect their suitability for parasite exploitation and thus influence prevalence and intensities/densities within populations. Nevertheless, thermal stress can induce different effects at the level of the individual host or parasite from that found at the population level, and consequently several outstanding questions remain (Box 3). However, the long-term effects of extreme weather on host–parasite systems remain more difficult to predict. The increased frequency of climatic events may favor those strains of parasites and hosts that are more tolerant to thermal stresses, although responses to cold stress in winter at mid- and high latitudes do not suggest 225
Opinion Box 3. Outstanding questions What are the precise physiological mechanisms underpinning the effects on parasites? Are there differences in effects on parasites between short-term and long-term exposures? How may the exact duration and timing of host acclimation to temperature extremes influence the effects on parasites? How exactly does inducement of host hibernation and the length of time in the torpid state influence the course of parasitic infections?
any form of selection is taking place. Therefore, the present research emphasis on ectothermic components of parasite life histories within vulnerable populations, although more likely to be interpreted and incorporated into predictive frameworks, can only reveal a small fraction of the effects on parasite dynamics. Without combining these ectothermic elements with further knowledge of the physiological thermodynamics of parasitic infections in endothermic hosts, there is a risk that predictions will fall short in providing a complete understanding of ecological host– parasite interactions during extreme temperature conditions under climate change, which in turn is required for a precise analysis of disease risk. References 1 Intergovernmental Panel on Climate Change (IPCC) (2013) Climate Change 2013: The Physical Science Basis, WMO, UNEF 2 Harvell, C.D. et al. (2002) Climate warming and disease risks for terrestrial and marine biota. Science 296, 2158–2162 3 Mordecai, E.A. et al. (2013) Optimal temperature for malaria transmission is drastically lower than previously predicted. Ecol. Lett. 16, 22–30 4 Boyles, J.G. et al. (2011) Adaptive thermoregulation in endotherms may alter responses to climate change. Integr. Comp. Biol. 51, 676–690 5 Fuller, A. et al. (2010) Physiological mechanisms in coping with climate change. Physiol. Biochem. Zool. 83, 713–720 6 Martinez, J. and Merino, S. (2011) Host–parasite interactions under extreme climatic conditions. Curr. Zool. 57, 390–405 7 McKechnie, A.E. and Wolf, B.O. (2010) Climate change increases the likelihood of catastrophic avian mortality events during extreme heat waves. Biol. Lett. 6, 253–256 8 Peterson, P.K. et al. (1991) Stress and pathogenesis of infectious disease. Rev. Infect. Dis. 13, 710–720 9 Lafferty, K.D. and Holt, R.D. (2003) How should environmental stress affect the population dynamics of disease? Ecol. Lett. 6, 654–664 10 Rohr, J.R. et al. (2013) Using physiology to understand climate-driven changes in disease and their implications. Conserv. Physiol. 1, 1–15 11 Amrein, Y.U. (1967) Effects of environmental temperature on Trypanosoma cruzi infection in mice. J. Parasitol. 53, 1160 12 McQuistion, T.E. (1979) Effect of temperature and clofibrate on Plasmodium berghei infection in mice. Am. J. Trop. Med. Hyg. 28, 12–14 13 Hayworth, A.M. et al. (1987) Effects of Plasmodium relictum on the metabolic rate and body temperature in canaries (Serinus canaries). J. Parasitol. 73, 850–853 14 Hamadto, H.H. et al. (1989) Effect of ambient temperature changes on chronic toxoplasmosis in rats. J. Egypt. Soc. Parasitol. 19, 527–532 15 Barnard, C.J. et al. (1996) Social status and resistance to disease in house mice (Mus musculus): status-related modulation of hormone responses in relation to immunity costs in different social and physical environments. Ethology 102, 63–84 16 Otieno, L.H. (1972) Influence of ambient temperature on course of experimental trypanosomiasis in mice. Ann. Trop. Med. Parasitol. 66, 15–24 17 Mathur, S.C. (1976) Effect of environmental temperature on Trypanosoma evansi infection in mice. Indian Vet. J. 53, 331–336 226
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18 Sen, D.K. et al. (1981) Trypanosoma musculi infections in two mouse strains exposed to various environmental temperatures. J. Parasitol. 67, 744–746 19 Evans, W.S. and Novak, M. (1983) Growth and development of Hymenolepis microstoma in mice acclimated to different environmental temperatures. Can. J. Zool. 61, 2899–2903 20 Huebert, T. et al. (1990) Hymenolepis diminuta: the effect of cold temperature exposure on infections in mice. Exp. Parasitol. 70, 398– 403 21 Novak, M. et al. (1986) Growth and development of Hymenolepis nana in mice maintained at different environmental temperatures. Int. J. Parasitol. 16, 13–17 22 Novak, M. (1979) Environmental temperature and the growth of Mesocestoides corti populations in mice. Int. J. Parasitol. 9, 429–433 23 Novak, M. (1978) Environmental temperature and the growth of Taenia crassiceps cysticerci in mice. Experientia 34, 1149 24 Novak, M. (1983) Growth of Echinococcus multilocularis in gerbils exposed to different environmental temperatures. Experientia 39, 414 25 Lightner, L.K. and Ulmer, M.J. (1974) Trichinella spiralis: effect of environmental temperature on mice. Exp. Parasitol. 35, 262–265 26 Lightner, L.K. (1975) Environmental temperature and the development of Schistosomatium douthitti in mice. J. Parasitol. 61, 972–973 27 Ichii, S. et al. (1990) Growth and fecundity of Schistosoma japonicum in mice maintained at different environmental temperatures. Jpn. J. Exp. Med. 60, 39–44 28 Haukisalmi, V. et al. (1988) Population dynamics of common and rare helminths in cyclic vole populations. J. Anim. Ecol. 57, 807–825 29 Cornell, S.J. et al. (2008) Seasonality, cohort-dependence and the development of immunity in a natural host–nematode system. Proc. R. Soc. B 275, 511–518 30 Hayward, A.D. et al. (2011) Natural selection on a measure of parasite resistance varies across ages and environmental conditions in a wild mammal. J. Evol. Biol. 24, 1664–1676 31 Simitch, T. et al. (1956) L’effet du sommeil hibernal sur Toxoplasma gondii chez des Citellus citellus infecte´s expe´rimentalement. Arch. Inst. Pasteur Alger. 34, 355–359 32 Noble, G.A. (1966) Stress and parasitism. IV. Cold stress and Entamoeba. Exp. Parasitol. 19, 264–268 33 Davis, S.D. (1969) Hibernation: intestinal protozoa populations in ground squirrels. Exp. Parasitol. 26, 156–165 34 Chute, R.M. (1960) The influence of hibernation on the development of Trichinella spiralis in the dormouse, Eliomys qercinus. J. Parasitol. 46 (Suppl.), 21–22 35 Chute, R.M. (1961) Infections of Trichinella spiralis in hibernating hamsters. J. Parasitol. 47, 25–29 36 Chute, R.M. and Covalt, D.B. (1960) The effect of body temperature on the development of Trichinella spiralis in bats. J. Parasitol. 46, 855– 858 37 Cahill, J.E. et al. (1967) Effect of hibernation on course of infection and immune response in Citellus tridecemlineatus infected with Nippostrongylus brasiliensis. J. Parasitol. 53, 110–115 38 Ford, B.R. (1972) Hymenolepis citelli: development and chemical composition in hypothermic ground squirrels. Exp. Parasitol. 32, 62–70 39 Ford, B.R. and Lang, B.Z. (1967) Fasciola hepatica in hibernating Citellus tridecemlineatus (Mitchell). J. Parasitol. 53, 1073 40 Carmichael, A.C. and Muchlinske, A.E. (1980) Survival of Shistosomatium douthitti during hibernation in the natural host, Zapus hudsonius. J. Parasitol. 66, 365–366 41 Hommel, M. et al. (1973) Le ha´mster d’Europe (Cricetus cricetus) hoˆle experimental nouveau de Schistosoma mansoni. Etude des effets de l’hibernation. Bull. Soc. Pathol. Exot. Filiales 66, 296–298 42 Lewert, R.M. (1970) Schistosomes. In Immunity to Parasitic Animals (Jackson, G.J. et al., eds), pp. 981–1008, Appleton-Century-Crofts 43 Gau, R.J. et al. (1999) Parasites in grizzly bears from the Central Canadian Arctic. J. Wildl. Dis. 35, 618–621 44 Callait, M-P. and Gauthier, D. (2000) Parasite adaptations to hibernation in Alpine marmots (Marmota marmot). In Life in the Cold (Heldmaier, G. and Klingenspor, M., eds), pp. 139–146, Springer 45 Coggins, J.R. et al. (1982) Seasonal changes and overwintering of parasites in the bat, Myotis lucifugus (Le Conte), in a Wisconsin hibernaculum. Am. Midl. Nat. 107, 305–315
Opinion 46 Sehgal, S. and Arora, S.K. (1987) Effect of temperature on Leishmania mexicana amazonensis induced lesions in hamsters. Indian J. Med. Res. 86, 25–30 47 Moyou-Somo, R. et al. (1978) Influence d’une ambiance thermique chaude sur l’e´volution du paludisme experimental de la Souris a` Plamodium berghei berghei. C. R. Hebd. Se´ances Acad. Sci. D 286, 993–996 48 Anderson, W.I. et al. (1976) Effects of high environmental temperatures on cecal coccidiosis. Poult. Sci. 55, 1429–1435 49 Moyou-Somo, R. et al. (1978) Modifications de Plasmodium berghei berghei chez la Souris maintenue dans une atmosphere chaude. C. R. Hebd. Se´ances Acad. Sci. D 286, 1315–1317 50 Lightner, L.K. (1977) Environmental heat stress and the development of Schistosoma mansoni in mice. Iowa State J. Res. 52, 5–7 51 Tribouley, J. et al. (1977) Influence de la temperature ambiante sur l’evolution de Schistosoma mansoni chez la souris. Ann. Parasitol. Hum. Comp. 52, 629–636 52 Eysker, M. et al. (2005) Consequences of the unusually warm and dry summer of 2003 in the Netherlands: poor development of free living stages, normal survival of infective larvae and long survival of adult gastrointestinal nematodes of sheep. Vet. Parasitol. 133, 313–321 53 Dimock, K.A. et al. (1991) Effect of elevated temperature on the antibody response of mice to Trypanosoma cruzi during the acute phase of infection. Infect. Immun. 59, 4377–4382 54 Ming, Z. and Davis, C.D. (2003) CD8+ lymphocytes required for enhanced survival of Trypanosoma cruzi-infected mice at elevated environmental temperature. J. Parasitol. 89, 630–632 55 Escobedo, G. et al. (2005) Parasite regulation by host hormones: an old mechanism of host exploitation? Trends Parasitol. 21, 588–593 56 Pennycuik, P.R. (1967) A comparison of the effects of a variety of factors on the metabolic rate of the mouse. Aust. J. Exp. Biol. Med. Sci. 45, 331– 346 57 Morley, N.J. (2011) Inbred laboratory cultures and natural trematode transmission under climate change. Trends Parasitol. 27, 286–287 58 Lochmiller, R.L. et al. (1994) Temporal variation in humoral and cellmediated immune response in a Sigmodon hispidus population. Ecology 75, 236–245
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59 Pyrovetsi, M. and Papazahariadou, M. (1995) Mortality factors of Dalmatian Pelicans (Pelecanus crispus) wintering in Macedonia, Greece. Environ. Conserv. 22, 345–351 60 Athanasiadou, S. (2012) Nutritional deficiencies and parasitic disease: lessons and advancements from rodent models. Vet. Parasitol. 189, 97– 103 61 Kristan, D.M. (2008) Calorie restriction and susceptibility to intact pathogens. Age 30, 147–156 62 Pautrizel, A-N. et al. (1977) Influence d’une ambiance thermique e´leve´e sur l’e´volution de la trypanosomiase expe´rimentale de la Souris. C. R. Hebd. Se´ances Acad. Sci. D 284, 2187–2190 63 Barnett, S.A. and Mount, L.E. (1967) Resistance to cold in mammals. In Thermobiology (Rose, A.H., ed.), pp. 411–477, Academic Press 64 Chaffee, R.R.J. and Roberts, J.C. (1971) Temperature acclimation in birds and mammals. Annu. Rev. Physiol. 33, 155–202 65 Kelley, K.W. (1980) Stress and immune function: a bibliographic review. Ann. Rech. Vet. 11, 445–478 66 Prendergast, B.J. et al. (2002) Periodic arousal from hibernation is necessary for initiation of immune responses in ground squirrels. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1054–R1062 67 Moore, S. et al. (2012) Predicting the effect of climate change on African trypanosomiasis: integrating epidemiology with parasite and vector biology. J. R. Soc. Interface 9, 817–830 68 Kolodny, M.H. (1940) The effect of environmental temperature upon experimental trypanosomiasis (T. cruzi) of rats. Am. J. Hyg. 32C, 21–23 69 Sesti-Costa, R. et al. (2012) Chronic cold stress in mice induces a regulatory phenotype in macrophages: correlation with increased 11b-hydroxysteroid dehydrogenase expression. Brain Behav. Immun. 26, 30–60 70 Sheppe, W.A. and Adams, J.R. (1957) The pathogenic effect of Trypanosoma duttoni in hosts under stress conditions. J. Parasitol. 43, 55–59 71 Arif, A.A. et al. (1999) Antibody response to heat shock proteins and histopathology in mice infected with Trypanosoma cruzi and maintained at elevated temperature. J. Parasitol. 85, 1089–1099 72 Govaerts, M. et al. (1986) Influence of heat stress on experimental Trypanosoma brucei brucei infection in mice. Ann. Soc. Belg. Med. Trop. 66, 161–166
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Temperature stress and parasitism of endothermic hosts under climate change Neil J. Morley and John W. Lewis School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey, TW20 0EX, UK
Climate change is a major threat to global environmental stability and is predicted to cause more frequent extreme weather events with higher levels of heat and cold stress. The physiological effects of such events on parasitic infections within endotherms are poorly studied and rarely considered in the context of climate change where an emphasis on ectothermic components of parasite life cycles (free-living stages and invertebrate hosts or vectors) predominates. However, thermal stress can affect parasite establishment, growth, fecundity, and development within endothermic hosts and may thus potentially influence transmission potential. Such changes can be caused by temperature effects on host physiological homeostasis, predominantly endocrine and immune systems, and may have wide implications for parasite epidemiology under extreme climatic events. Parasitism of endotherms under a changing climate Climate change is one of the greatest threats to global environmental and economic stability, predicted to cause widespread changes in temperature and precipitation with an increased frequency of severe weather conditions [1]. The most recent IPCC (Intergovernmental Panel on Climate Change) assessment [1] considers that there will be more frequent hot and fewer cold temperature extremes on a daily and seasonal basis. Heat waves are very likely to occur with a higher frequency and duration, although occasional cold winter extremes will continue to arise. Temperature effects on animals are therefore one of the primary variables of scientific concern, either through rises in average temperature conditions or by sudden thermal changes associated with an extreme climatic event (see Glossary) such as heat waves, droughts, and cold snaps. For parasites, attention has focused on important modifications to free-living stage viability and interactions with ectothermic hosts or vectors [2], especially associated with Corresponding author: Morley, N.J. ([email protected]). Keywords: climate change; endotherms; parasites; physiology; endocrinology; immunology. 1471-4922/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2014.01.007
changes in geographical distribution of insect vectors such as mosquitoes [3]. There is no doubt that this focus is a research priority; nevertheless, an emphasis almost exclusively on ectothermic components ignores the direct effects of temperature on endothermic hosts within the life cycles of parasites. In particular, cold and heat stress which accompany changes in temperature under extreme climatic events may induce trauma that can influence physiological and endocrinological homeostasis of endotherms (Box 1). An increased frequency of such events is one of the most detrimental yet understudied aspects of climate change on endotherms [4,5], yet seldom considered in parasitology [6]. These often short but extreme temperature shifts impose different demands on endotherms than a slowly warming climate [4], and during the past decade may be associated with increased reports of mass die-offs [7]. Such changes in the physiological homeostasis of endotherms may seriously affect their suitability as hosts. Under laboratory conditions, stress is known to influence the occurrence and virulence of a range of infectious diseases in endothermic hosts [8]. In particular, the physiological dynamics of many protozoan and metazoan parasitic infections have been negatively or positively affected by temperature stress, although this has rarely been considered at the population level despite the implications for parasite epidemiology. Nevertheless, there are a diverse range of stress effects at the levels of individual host or
Glossary Ectotherm: an animal that is dependent on the external environment to maintain its body temperature. Endotherm: an animal that generates heat to maintain its body temperature independent of, and typically above, its environment. Extreme climatic events: these are events at the boundaries of the range of weather experienced in the past and can include severe episodes such as heat waves, droughts, intense rainfall, or cold snaps. Heterothermy: endotherms that can switch between an ectothermic or endothermic physiological state dependent on life history requirements, typically found in animals that hibernate in response to external conditions. Homeothermy: animals that maintain a stable body temperature regardless of external environmental conditions. Physiological homeostasis: the ability of an animal to maintain a stable internal environment by physiological processes. Thermoneutral zone (TNZ): this represents the optimal range of environmental temperatures for an endotherm, where the basal rate of heat production is in equilibrium with the rate of heat loss to the external environment and the organism does not have to use large amounts of energy to control its body temperature. Trends in Parasitology, May 2014, Vol. 30, No. 5
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Box 1. Effects of temperature stress on endotherms With the exception of migratory and hibernatory cues, direct thermal impacts of climate change are rarely described for endotherms [4]. However, laboratory studies have determined that endothermic metabolic rates are substantially higher than those of ectotherms and metabolic heat production, which is regulated in response to environmental temperature fluctuations, constitutes much of the energy expended by endotherms when environmental temperatures deviate from the TNZ. Therefore, thermal variations associated with climate change are likely to strongly influence endotherms and this may be fundamentally different from effects on ectotherms [4]. Depending on the thermoregulatory characteristics of individuals, populations, or species, energy expenditure, which maintains a constant body temperature, may rise as ambient temperature increasingly diverges from the TNZ of endotherms, thereby lessening the energy available for other fundamental biological functions [4]. In cold environments, homeothermic endotherms change the extent of thermal insulation (fur or feathers) and peripheral blood flow with increased food consumption as neuroendocrine receptors respond to changing thermal conditions. Elevated levels of adrenocortical hormones are produced, and there is greater activity of the pituitary and thyroid glands. Increased endocrine activity creates immunosuppressive and anti-inflammatory effects, thus suppressing many aspects of the immune system. Although endotherms become less active, they maintain an elevated level of heat production, accompanied by changes in the enzyme activities of muscles, liver, and other organs. Prolonged cold exposure can lead to the enlargement of more active organs such as the heart, intestine, liver, kidney, and thyroid and adrenal glands [63–65].
population which can result in complex interactions between stress and disease [9]. However, physiological mechanisms and thermal biology theory remain poorly integrated into climate change–disease studies [10]. Indeed, there has been a tendency to ignore endotherm physiological responses to climate change and to consider fluctuations in levels of infections a product of the effects on ectothermic components of their life cycles alone. However, both endothermic hosts and their parasites function optimally within certain physiological temperature ranges, the thermoneutral zone (TNZ), and perform gradually more poorly the further the thermal environment deviates from these conditions. Most host–parasite interactions are mediated by physiological responses which, in turn, can be influenced by environmental conditions such as climate. Therefore, only by understanding endotherm physiology in combination with ectothermic aspects of host–parasite relationships will a robust mechanistic understanding of how climate change affects parasitic infections in host populations be attained [10]. In this review, we present evidence from laboratory studies of the direct effects of cold and heat stress on parasites within endothermic hosts. In these conditions, animals are normally maintained in stable ambient environments at temperatures typically ranging from 228C to 258C and exposed to experimental high or low temperatures that constitute thermal stress. In natural environments, animals will be found in habitats with a range of different ambient temperature conditions. Consequently, thermal stress may occur at different temperatures from those found under laboratory conditions. However, the types of physiological responses of endotherms to thermal stress remain constant and therefore the effects on parasite viability found in laboratory studies will be reflected in the natural environment. Under a changing climate, where 222
The ability of some heterothermic endotherms to enter hibernation during extended cold periods may place them at a competitive advantage over homeothermic ones [4]. Heterotherms lower their body temperature, decreasing the level of metabolism and other aspects of functional biology required for a given degree of thermal insulation. Nevertheless, periodic arousal from hibernation is required to activate a dormant immune system for combating any infectious agents [66]. The associated marked energetic costs may in part reflect a trade-off between maintaining a long-term energy balance as well as contending with parasitic infections. Nevertheless, different species of heterotherms, whose populations may thermoregulate independently to similar changes in climate, exhibit diverse levels of metabolic rates and energy expenditure during hibernation [4], which may influence their immunocompetence. By contrast, endotherms exposed to a hot environment decrease their metabolism, oxygen uptake, and food consumption due to the responses of neuroendocrine mechanisms to changing thermal conditions. The lowered food intake, in turn, influences thyroid activity, leading to a reduction in associated hormonal levels. The production of testosterone is also inhibited, whereas plasma corticoids initially increase and then decrease following prolonged exposure. Such reduced endocrine activity appears to benefit many aspects of the immune system, allowing optimal responses to challenges. There is a decline in weight of a number of internal organs and a reduction in oxidative enzyme activity, particularly in the liver. The level of dermal blood flow is adjusted to increase heat loss, largely at the expense of circulation to other regions of the body [56,64,65].
the frequency of extreme high temperatures may increase whilst those of cold temperature extremes decrease, we consider that overlooking these thermal stress effects at the individual level may undermine attempts to create predictive frameworks of the influence of climate change on host–parasite dynamics at the population level. Cold extremes Under the stress caused by experimental cold (4–108C air temperature) exposure of infected endotherms, changes to parasite viability can be separated into two groups dependent on whether the host is hibernatory (heterothermic) or non-hibernatory (homeothermic). In homeothermic hosts (mice, rats, canaries), protozoan infections demonstrate a general trend of increased parasitemia with corresponding rises in host pathology and mortality [11–14], although other factors such as social status can moderate hormone and immune responses, influencing parasite levels at these temperatures [15]. Furthermore, a more complex pattern of responses associated with host and parasite strains emerges from studies with trypanosomes [11,16–18] (Box 2). For helminths, experimental cold stress induces a greater range of effects in homeothermic hosts (mice and gerbils). Many tapeworm species, including both adult and metacestode stages, show patterns of higher prevalences more prominently in male mice [19–22]. By contrast, some metacestode species demonstrate lower parasite intensity and growth [23] or remained unaffected [24]. Differences between individual strains of hosts are also apparent, as in the case of the nematode Trichinella spiralis, which demonstrates reduced adult intensity in the intestine of one mouse strain but remains unaffected in another [25]. By contrast, both Schistosoma japonicum and Schistosomatium douthitti show neither differences
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Box 2. Trypanosomes: a case study Trypanosomes are kinetoplastid eukaryote parasites of vertebrates, mainly transmitted by blood-feeding invertebrates, and are likely to increase in incidence or expand their geographical range under climate change [67]. Most species live in the blood and tissue fluids of endothermic hosts and the effects of temperature stress on these parasites have been extensively studied in the laboratory. In cold environments (108C) the parasite load of Trypanosoma cruzi-infected rodents generally increases along with a corresponding rise in host mortality rates [11,68]. Exposure to 48C for 4 h also increases parasitemia, but host survival rates are not substantially altered [69]. Furthermore, ‘non-pathogenic’ species such as Trypanosoma duttoni become virulent in rodents when exposed to these temperature regimes and a low food supply [70]. Nevertheless, such responses are not consistent across all studies, probably associated with host/parasite species-specific and strain-specific variations. For example, unlike T. cruzi exposure of mice infected with Trypanosoma evansi or Trypanosoma brucei to 48C results in a variable reduction in parasite load, but a comparable host survival rate with mice maintained at 22–268C [16,17]. Similarly, two strains of mice show different levels of infections with Trypanosoma musculi at 108C, either reducing parasitemia or remaining largely unchanged [18]. Trypanosome-infected rodents maintained at high ambient laboratory temperatures (358C) over a number of months show reduced parasite loads, cardiac and skeletal muscle pathology, and lowered host mortality rates [11,16,68,71]. Rodents already showing high
in parasite intensity nor infection success compared with mice maintained at room temperature [26,27]. Nevertheless, S. japonicum demonstrates delayed fecundity, suggesting that growth and development are slower under these conditions [28]. Under natural environments of winter cold extremes, there have been only limited studies on parasite viability in homeotherms. Nevertheless, it is apparent that these conditions influence host immune response which, in turn, changes helminth occurrence [28–30]. In heterothermic animals, experimental cold stress during periods of hibernation may affect parasites directly due to the drop in body temperature and indirectly through changes to physiological homeostasis of the host. Studies on Toxoplasma gondii infections in squirrels found that hibernation prolonged the survival of infected hosts because it appeared that the lowered body temperature of the hosts inhibited multiplication of the parasite [31]. However, Entamoeba infections demonstrate more variable responses in the intestine of hibernating squirrels with an increase in parasitemia [32] or a complete loss of infection [33] during this temperature exposure. Helminths also demonstrate variable responses in heterothermic hosts. T. spiralis is uniformly negatively affected in many hibernatory species (dormice, hamsters, bats) with nematode development either reduced or completely prevented during the host’s phase of torpidity. The intensity of infection is also lower in hosts induced into hibernation within 2 days of experimental infection compared with those induced 15 days later [34–36]. By contrast, prolonged hibernation of ground squirrels results in the loss of most infections with Nippostrongylus brasiliensis, whether induced immediately following experimental infection or in hosts with well-established adult worms [37]. The intestinal cestode Hymenoplepis citelli also shows reduced growth and development in ground squirrels
parasitemia at room temperatures rapidly become aparasitemic after transfer to 358C [16,71], and when parasite numbers decline to undetectable levels and the hosts return to room temperature, no relapse of parasitemia or mortality rates are detected [71]. Nevertheless, other studies have found that heat stress has little effect on parasite levels [72]. The number of parasites harbored in a host at these high temperatures can vary substantially between different rodent [18,62] and parasite strains [16] and, in particular, variations in parasite strains can cause effects ranging from almost no change in parasitemia to a rapid elimination of parasites resulting in ‘self cure’ [16,17,72]. This reduction in parasitemia appears to be associated with a change in the immunological response of the host as well as direct effects on the trypanosomes themselves. It is apparent that there is a significant optimization of both parasite-specific and nonspecific cellular and humoral immune responses [53,54,72], providing an elevated level of protection. Although changes in immune responses appear to be the main factor in determining parasitemia under laboratory conditions, high temperatures also appear to directly affect the parasites. This results in increased levels of morphological deformities and lowered reproduction, due to sensitivity to reduced oxygen uptake of hosts under these conditions [16,56]. However, it remains to be determined if these changes reported from laboratory studies are replicated under natural conditions found during extreme climatic events.
during hibernation [38], whereas certain trematode species seem to demonstrate more mixed responses, which are probably related to the stage of development when hibernation is induced and/or dependent on the strain of parasite and host. For example, Fasciola hepatica demonstrates reduced development and maturation if squirrel hibernation occurs before worms have migrated to the bile duct, whereas worms do not survive if hibernation is induced following establishment within the bile duct [39]. For schistosomes such as Schistosoma mansoni and S. douthitti, there are no differences in levels of infection in a range of hibernating host species (meadow jumping mouse, squirrels, hamsters) compared with room temperature controls, even if infections occurred before or after acclimation to low temperatures or over prolonged periods of hibernation. Schistosomes will also develop and produce viable eggs in hibernating hosts, although developmental rates are slower, with some adult worms surviving over a 58-day hibernation period without any apparent abnormalities [40] (D.W. Dery, PhD thesis, Florida State University, 1961). By contrast, the developmental rates of other strains of S. mansoni remain unchanged in hibernating hamsters compared with those maintained at room temperature [41] or may be rapidly immobilized in squirrels induced into hibernation, with adult worms accumulating in the liver where they are soon destroyed by leukocytes [42]. Studies under natural conditions also support the idea of a complex but generally negative effect of hibernation on helminths with a reduction in the occurrence of some species and a slower growth of others dependent on the hibernation habits of the host [43–45]. Heat extremes Infected endotherms under experimental heat stress (35–368C air temperature for mammals, 328C for birds) cause numerous changes in the viability of their parasites. In general, most protozoans studied are negatively affected 223
Opinion by such conditions with a reduction in parasitemia and pathology and an increase in host (mouse, hamsters) survival [11,46–47] (Box 2). High temperatures, at least in birds, need to be maintained for a minimum of 2 days for the viability of Eimeria species to be reduced [48], whereas in mice a lower temperature of 308C did not have a detrimental effect on the development of Leishmania braziliensis pifanoi (Z. Hayatee, PhD thesis, University of London, 1971). This suggests that both a minimum temperature and duration threshold need to be achieved before such negative effects become apparent. Differences in both parasite and host strains can influence the extent of any negative effects [16,17,47]. However, exceptions occur as in the case of T. gondii where an increase in pathology and a reactivation and spread of cysts was found in the brains of heat-stressed rats [14]. It is possible that these generally negative effects on parasites are not associated with a decline in their functional biology, particularly considering that Plasmodium berghi berghi has an increased synthesis of DNA in mice exposed to higher temperatures, indicating elevated multiplication and growth [49], thus suggesting that an improved host immune response may potentially be the primary variable. Helminths demonstrate a more complex response to these experimental temperature stresses. Mice acclimated to high temperature for 5 days became less susceptible to a subsequent percutaneous infection with the trematodes S. douthitti and S. mansoni [26,50]. However, a 10-day acclimation period did not significantly affect susceptibility to a subcutaneous infection with a different strain of S. mansoni. By contrast, mice infected subcutaneously at room temperature and then subjected to 358C or higher temperatures showed significantly lower intensities after only 1 day of heat stress and were found to be parasite-free after 6 weeks. Further studies showed that S. mansoni was only susceptible to such stresses during temperature exposures of 1–15 days post-infection but not from days 10 to 20, suggesting that the schistosomula, migratory larval stages that travel through the blood vessels to the liver, were most vulnerable to these conditions [51]. This narrow period of post-infection susceptibility may be a factor in the contradictory effects of heat stress on S. japonicum infections where levels of infections in mice remain unaffected, but by 7 weeks post-infection both male and female worms are shorter in length and the egg burden in host tissues was reduced compared with controls [27]. Cestodes such as hymenolepids are negatively affected by increased temperature, resulting in a reduction in growth, development, and egg production, which occurred more prominently in male mice [19,21]. Similarly, mice harbor lower burdens of Taenia crassiceps and Mesocestoides corti, and these tapeworms also show reduced growth, especially in male hosts [22,23]. By contrast, Echinococcus multilocularis had a higher growth rate and proliferation of cysts in gerbils at high temperatures [24]. Such a positive effect is also shown by the nematode T. spiralis in mice, with significantly higher numbers of adult worms, but this is dependent on the mouse strain [25]. Under natural conditions of heat extremes, it is difficult to disentangle thermal effects on free-living stages nor on ectothermic hosts or vectors from those derived directly in 224
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endothermic hosts. Nevertheless, the adult nematode Haemonchus contortus in sheep survived longer with higher fecal egg counts during an unusual summer of hot dry conditions [52], which may be associated with changes in host physiology. Further studies on parasite viability in endothermic hosts under natural heat extremes are therefore required to fully elucidate the range of potential effects. Effects of host physiological mechanisms on parasites It is generally considered that, because under most circumstances host body temperature does not substantially vary, changes in the levels of infections under experimental temperature stress are primarily due to thermal modifications in host physiology, particularly the endocrine and immune systems [19,20,25,37,53,54], although it remains to be determined if such results are replicated under natural conditions. Direct effects of environmental temperatures on parasites, however, cannot be completely ruled out, especially in heterothermic hosts under cold stress, but that we consider are likely to be secondary to indirect effects caused by changes in host physiological homeostasis (Box 1), radically changing conditions for parasites in a manner beyond those capable by thermal effects alone. Nevertheless, the exact physiological mechanisms influencing parasites under these conditions are poorly understood, but much can be inferred from known endocrinological and immunological changes in endotherm physiology (Box 1). These thermally induced changes can be placed in the context of known fluctuations in the host endocrine system that can either directly influence the functional biology of parasites, by facilitating infections and increasing growth and reproduction rates, or indirectly by altering the efficiency of the immune system [55] and thus altering the rate of parasite mortality. In particular, both adrenal hormones and sex steroids are potent immunomodulators, whose influence on the immune system are moderated by host sex and age [55]. Thus, the substantial changes that occur in the endocrine system under cold and heat stress (Box 1) can influence levels of parasitic infections. However, the exact physiological pathways that result in changes to parasitism remain difficult to determine because they will vary from one parasite species to another, dependent on the host organs and tissues they reside in or migrate through and the demands of the individual host–parasite relationship, which itself can be influenced by the intensity of infection. Nevertheless, although endocrine and immune changes appear to be the principal influence on parasites, other physiological variations may be of secondary importance. For example, lower levels of oxygen uptake under heat stress [56] may affect the viability of sensitive protozoan species, whereas increased or decreased food consumption and associated intestinal motility under cold or heat stress could influence growth and development of gut parasites [20]. It is apparent that the extent of temperature effects is highly dependent on the strain of parasite and host. In most cases, the above experiments were undertaken on laboratory strains that had been maintained for many years, and due to extensive inbreeding some caution must
Opinion therefore be taken when extrapolating data derived from these sources to the natural environment [57]. Similarly, conditions in which each experiment was undertaken are unlikely to be exactly the same from one study to another. However, regardless of the circumstances of individual experiments hosts were subjected to a level of temperature stress that deviated from long-term maintenance in ambient conditions, which closely reflected their TNZ. Nevertheless, from the limited evidence available, results obtained under laboratory conditions appear concordant at least with those obtained from natural sources under cold stress [43,44]. Potential implications for parasite transmission Temperature variations have a complex and relatively unappreciated effect on the course of parasitic infections within endothermic hosts at the individual level, but can such changes influence the epidemiology of parasites at the population level under extreme climatic events? Cold temperatures are regular seasonal features of mid- and highlatitude habitats. These conditions during winter can cause complex effects on parasite infections of homeotherms [30], even though transmission is interrupted in the absence of ectothermic hosts or vectors. At least some changes can be attributed to alterations in host immunity [58] and in turn with variations in the endocrine system. A reduction in the frequency of cold extremes may therefore change the physiological dynamics of host–parasite interactions over the winter, which may increase or decrease parasite occurrence within endothermic host populations. Such changes may be additionally impacted by an expanded seasonal transmission window through ectothermic components of parasite life cycles during milder temperature conditions in the spring and autumn. Nevertheless, alternative mechanisms influencing parasitism in endotherms need to be considered. For example, during harsh winters the availability of food for homeotherms may be reduced, which can have lethal consequences for animals [59]. Reduced food intake can also affect endotherm physiology, particularly immunity, changing their susceptibility to infections [60,61], but a reduction in the frequency of cold winter extremes under climate change [1] is likely to reduce the influence of such factors. Milder winters, associated with a decrease in the frequency of cold temperature extremes under climate change in mid- and high-latitude habitats [1], will also impact upon heterotherms by altering the pattern and duration of hibernation. Changes in the level of host thermoregulation, in turn, may reduce the effects on parasites within hibernatory animals, thereby changing the dynamics of the overwintering host–parasite relationship. Heat stress, associated with short-term extreme climatic events, may influence host endocrine and immune systems with consequent negative or positive effects on parasites. Under laboratory conditions, many parasites have lowered intensities/densities and reduced development and fecundity, although a smaller number of species or strains demonstrated the opposite. In addition, reduced feeding rates of endotherms at high environmental temperatures (Box 1) may lower the risk of infection from trophic-transmitted parasites. Under natural conditions,
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any change in the prevalence and intensity/density of parasites may, in the short-term, change both the health and alter transmission within host populations. An increased frequency of extreme climatic events and temperature stress could result in a persistent strain on parasite populations, potentially increasing the likelihood of long-term changes in levels of infection, particularly when combined with the impact such events are likely to have on ectothermic hosts or vectors. Nevertheless, wide variations in the effects of temperature stress associated with the type and strains of parasites or hosts exist, which must also be considered in the context of the many potential pathways that fluctuations in the endocrine and immune systems of the hosts may influence parasites. Such pathways will vary according to species, location within the host, and the nutritional demands and pathological effects the parasite induces in the host. Such complex physiological interactions between host and parasite under temperature stress suggest that the thermal impact associated with extreme climatic events may be patchy on a regional or local scale. Concluding remarks Optimal physiological temperature ranges (TNZ) exist for both endothermic hosts and their parasites. As environmental temperature conditions deviate from the TNZ, both organisms begin to function less well. Thus, extreme climatic events resulting in temperature stress have the potential to significantly influence levels of parasitic infections in endotherms. Under laboratory conditions, extreme environmental temperatures alter the physiology of endothermic hosts, thereby either benefiting or hindering parasite survival, development, or fecundity. Nevertheless, stress induced by temperature causes a complex series of changes in host–parasite relationships dependent on a range of factors including duration and timing of exposure in relation to parasite development, the particular strain of parasite or host, the site of infection within the host, and the thermoregulatory characteristics of individual host species. However, the role of host acclimation to temperature extremes and its influence on parasite viability still remains to be fully elucidated [9]. Acclimation appears to have little influence under some conditions but can play a pivotal role in other conditions [26,27,50,62]. Greater consistency in experimental design of future laboratory studies may provide more obvious patterns in responses of parasites to thermal stress in endothermic hosts becoming apparent. Under natural conditions, physiological changes of the endotherm host during extreme climatic events may affect their suitability for parasite exploitation and thus influence prevalence and intensities/densities within populations. Nevertheless, thermal stress can induce different effects at the level of the individual host or parasite from that found at the population level, and consequently several outstanding questions remain (Box 3). However, the long-term effects of extreme weather on host–parasite systems remain more difficult to predict. The increased frequency of climatic events may favor those strains of parasites and hosts that are more tolerant to thermal stresses, although responses to cold stress in winter at mid- and high latitudes do not suggest 225
Opinion Box 3. Outstanding questions What are the precise physiological mechanisms underpinning the effects on parasites? Are there differences in effects on parasites between short-term and long-term exposures? How may the exact duration and timing of host acclimation to temperature extremes influence the effects on parasites? How exactly does inducement of host hibernation and the length of time in the torpid state influence the course of parasitic infections?
any form of selection is taking place. Therefore, the present research emphasis on ectothermic components of parasite life histories within vulnerable populations, although more likely to be interpreted and incorporated into predictive frameworks, can only reveal a small fraction of the effects on parasite dynamics. Without combining these ectothermic elements with further knowledge of the physiological thermodynamics of parasitic infections in endothermic hosts, there is a risk that predictions will fall short in providing a complete understanding of ecological host– parasite interactions during extreme temperature conditions under climate change, which in turn is required for a precise analysis of disease risk. References 1 Intergovernmental Panel on Climate Change (IPCC) (2013) Climate Change 2013: The Physical Science Basis, WMO, UNEF 2 Harvell, C.D. et al. (2002) Climate warming and disease risks for terrestrial and marine biota. Science 296, 2158–2162 3 Mordecai, E.A. et al. (2013) Optimal temperature for malaria transmission is drastically lower than previously predicted. Ecol. Lett. 16, 22–30 4 Boyles, J.G. et al. (2011) Adaptive thermoregulation in endotherms may alter responses to climate change. Integr. Comp. Biol. 51, 676–690 5 Fuller, A. et al. (2010) Physiological mechanisms in coping with climate change. Physiol. Biochem. Zool. 83, 713–720 6 Martinez, J. and Merino, S. (2011) Host–parasite interactions under extreme climatic conditions. Curr. Zool. 57, 390–405 7 McKechnie, A.E. and Wolf, B.O. (2010) Climate change increases the likelihood of catastrophic avian mortality events during extreme heat waves. Biol. Lett. 6, 253–256 8 Peterson, P.K. et al. (1991) Stress and pathogenesis of infectious disease. Rev. Infect. Dis. 13, 710–720 9 Lafferty, K.D. and Holt, R.D. (2003) How should environmental stress affect the population dynamics of disease? Ecol. Lett. 6, 654–664 10 Rohr, J.R. et al. (2013) Using physiology to understand climate-driven changes in disease and their implications. Conserv. Physiol. 1, 1–15 11 Amrein, Y.U. (1967) Effects of environmental temperature on Trypanosoma cruzi infection in mice. J. Parasitol. 53, 1160 12 McQuistion, T.E. (1979) Effect of temperature and clofibrate on Plasmodium berghei infection in mice. Am. J. Trop. Med. Hyg. 28, 12–14 13 Hayworth, A.M. et al. (1987) Effects of Plasmodium relictum on the metabolic rate and body temperature in canaries (Serinus canaries). J. Parasitol. 73, 850–853 14 Hamadto, H.H. et al. (1989) Effect of ambient temperature changes on chronic toxoplasmosis in rats. J. Egypt. Soc. Parasitol. 19, 527–532 15 Barnard, C.J. et al. (1996) Social status and resistance to disease in house mice (Mus musculus): status-related modulation of hormone responses in relation to immunity costs in different social and physical environments. Ethology 102, 63–84 16 Otieno, L.H. (1972) Influence of ambient temperature on course of experimental trypanosomiasis in mice. Ann. Trop. Med. Parasitol. 66, 15–24 17 Mathur, S.C. (1976) Effect of environmental temperature on Trypanosoma evansi infection in mice. Indian Vet. J. 53, 331–336 226
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18 Sen, D.K. et al. (1981) Trypanosoma musculi infections in two mouse strains exposed to various environmental temperatures. J. Parasitol. 67, 744–746 19 Evans, W.S. and Novak, M. (1983) Growth and development of Hymenolepis microstoma in mice acclimated to different environmental temperatures. Can. J. Zool. 61, 2899–2903 20 Huebert, T. et al. (1990) Hymenolepis diminuta: the effect of cold temperature exposure on infections in mice. Exp. Parasitol. 70, 398– 403 21 Novak, M. et al. (1986) Growth and development of Hymenolepis nana in mice maintained at different environmental temperatures. Int. J. Parasitol. 16, 13–17 22 Novak, M. (1979) Environmental temperature and the growth of Mesocestoides corti populations in mice. Int. J. Parasitol. 9, 429–433 23 Novak, M. (1978) Environmental temperature and the growth of Taenia crassiceps cysticerci in mice. Experientia 34, 1149 24 Novak, M. (1983) Growth of Echinococcus multilocularis in gerbils exposed to different environmental temperatures. Experientia 39, 414 25 Lightner, L.K. and Ulmer, M.J. (1974) Trichinella spiralis: effect of environmental temperature on mice. Exp. Parasitol. 35, 262–265 26 Lightner, L.K. (1975) Environmental temperature and the development of Schistosomatium douthitti in mice. J. Parasitol. 61, 972–973 27 Ichii, S. et al. (1990) Growth and fecundity of Schistosoma japonicum in mice maintained at different environmental temperatures. Jpn. J. Exp. Med. 60, 39–44 28 Haukisalmi, V. et al. (1988) Population dynamics of common and rare helminths in cyclic vole populations. J. Anim. Ecol. 57, 807–825 29 Cornell, S.J. et al. (2008) Seasonality, cohort-dependence and the development of immunity in a natural host–nematode system. Proc. R. Soc. B 275, 511–518 30 Hayward, A.D. et al. (2011) Natural selection on a measure of parasite resistance varies across ages and environmental conditions in a wild mammal. J. Evol. Biol. 24, 1664–1676 31 Simitch, T. et al. (1956) L’effet du sommeil hibernal sur Toxoplasma gondii chez des Citellus citellus infecte´s expe´rimentalement. Arch. Inst. Pasteur Alger. 34, 355–359 32 Noble, G.A. (1966) Stress and parasitism. IV. Cold stress and Entamoeba. Exp. Parasitol. 19, 264–268 33 Davis, S.D. (1969) Hibernation: intestinal protozoa populations in ground squirrels. Exp. Parasitol. 26, 156–165 34 Chute, R.M. (1960) The influence of hibernation on the development of Trichinella spiralis in the dormouse, Eliomys qercinus. J. Parasitol. 46 (Suppl.), 21–22 35 Chute, R.M. (1961) Infections of Trichinella spiralis in hibernating hamsters. J. Parasitol. 47, 25–29 36 Chute, R.M. and Covalt, D.B. (1960) The effect of body temperature on the development of Trichinella spiralis in bats. J. Parasitol. 46, 855– 858 37 Cahill, J.E. et al. (1967) Effect of hibernation on course of infection and immune response in Citellus tridecemlineatus infected with Nippostrongylus brasiliensis. J. Parasitol. 53, 110–115 38 Ford, B.R. (1972) Hymenolepis citelli: development and chemical composition in hypothermic ground squirrels. Exp. Parasitol. 32, 62–70 39 Ford, B.R. and Lang, B.Z. (1967) Fasciola hepatica in hibernating Citellus tridecemlineatus (Mitchell). J. Parasitol. 53, 1073 40 Carmichael, A.C. and Muchlinske, A.E. (1980) Survival of Shistosomatium douthitti during hibernation in the natural host, Zapus hudsonius. J. Parasitol. 66, 365–366 41 Hommel, M. et al. (1973) Le ha´mster d’Europe (Cricetus cricetus) hoˆle experimental nouveau de Schistosoma mansoni. Etude des effets de l’hibernation. Bull. Soc. Pathol. Exot. Filiales 66, 296–298 42 Lewert, R.M. (1970) Schistosomes. In Immunity to Parasitic Animals (Jackson, G.J. et al., eds), pp. 981–1008, Appleton-Century-Crofts 43 Gau, R.J. et al. (1999) Parasites in grizzly bears from the Central Canadian Arctic. J. Wildl. Dis. 35, 618–621 44 Callait, M-P. and Gauthier, D. (2000) Parasite adaptations to hibernation in Alpine marmots (Marmota marmot). In Life in the Cold (Heldmaier, G. and Klingenspor, M., eds), pp. 139–146, Springer 45 Coggins, J.R. et al. (1982) Seasonal changes and overwintering of parasites in the bat, Myotis lucifugus (Le Conte), in a Wisconsin hibernaculum. Am. Midl. Nat. 107, 305–315
Opinion 46 Sehgal, S. and Arora, S.K. (1987) Effect of temperature on Leishmania mexicana amazonensis induced lesions in hamsters. Indian J. Med. Res. 86, 25–30 47 Moyou-Somo, R. et al. (1978) Influence d’une ambiance thermique chaude sur l’e´volution du paludisme experimental de la Souris a` Plamodium berghei berghei. C. R. Hebd. Se´ances Acad. Sci. D 286, 993–996 48 Anderson, W.I. et al. (1976) Effects of high environmental temperatures on cecal coccidiosis. Poult. Sci. 55, 1429–1435 49 Moyou-Somo, R. et al. (1978) Modifications de Plasmodium berghei berghei chez la Souris maintenue dans une atmosphere chaude. C. R. Hebd. Se´ances Acad. Sci. D 286, 1315–1317 50 Lightner, L.K. (1977) Environmental heat stress and the development of Schistosoma mansoni in mice. Iowa State J. Res. 52, 5–7 51 Tribouley, J. et al. (1977) Influence de la temperature ambiante sur l’evolution de Schistosoma mansoni chez la souris. Ann. Parasitol. Hum. Comp. 52, 629–636 52 Eysker, M. et al. (2005) Consequences of the unusually warm and dry summer of 2003 in the Netherlands: poor development of free living stages, normal survival of infective larvae and long survival of adult gastrointestinal nematodes of sheep. Vet. Parasitol. 133, 313–321 53 Dimock, K.A. et al. (1991) Effect of elevated temperature on the antibody response of mice to Trypanosoma cruzi during the acute phase of infection. Infect. Immun. 59, 4377–4382 54 Ming, Z. and Davis, C.D. (2003) CD8+ lymphocytes required for enhanced survival of Trypanosoma cruzi-infected mice at elevated environmental temperature. J. Parasitol. 89, 630–632 55 Escobedo, G. et al. (2005) Parasite regulation by host hormones: an old mechanism of host exploitation? Trends Parasitol. 21, 588–593 56 Pennycuik, P.R. (1967) A comparison of the effects of a variety of factors on the metabolic rate of the mouse. Aust. J. Exp. Biol. Med. Sci. 45, 331– 346 57 Morley, N.J. (2011) Inbred laboratory cultures and natural trematode transmission under climate change. Trends Parasitol. 27, 286–287 58 Lochmiller, R.L. et al. (1994) Temporal variation in humoral and cellmediated immune response in a Sigmodon hispidus population. Ecology 75, 236–245
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59 Pyrovetsi, M. and Papazahariadou, M. (1995) Mortality factors of Dalmatian Pelicans (Pelecanus crispus) wintering in Macedonia, Greece. Environ. Conserv. 22, 345–351 60 Athanasiadou, S. (2012) Nutritional deficiencies and parasitic disease: lessons and advancements from rodent models. Vet. Parasitol. 189, 97– 103 61 Kristan, D.M. (2008) Calorie restriction and susceptibility to intact pathogens. Age 30, 147–156 62 Pautrizel, A-N. et al. (1977) Influence d’une ambiance thermique e´leve´e sur l’e´volution de la trypanosomiase expe´rimentale de la Souris. C. R. Hebd. Se´ances Acad. Sci. D 284, 2187–2190 63 Barnett, S.A. and Mount, L.E. (1967) Resistance to cold in mammals. In Thermobiology (Rose, A.H., ed.), pp. 411–477, Academic Press 64 Chaffee, R.R.J. and Roberts, J.C. (1971) Temperature acclimation in birds and mammals. Annu. Rev. Physiol. 33, 155–202 65 Kelley, K.W. (1980) Stress and immune function: a bibliographic review. Ann. Rech. Vet. 11, 445–478 66 Prendergast, B.J. et al. (2002) Periodic arousal from hibernation is necessary for initiation of immune responses in ground squirrels. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1054–R1062 67 Moore, S. et al. (2012) Predicting the effect of climate change on African trypanosomiasis: integrating epidemiology with parasite and vector biology. J. R. Soc. Interface 9, 817–830 68 Kolodny, M.H. (1940) The effect of environmental temperature upon experimental trypanosomiasis (T. cruzi) of rats. Am. J. Hyg. 32C, 21–23 69 Sesti-Costa, R. et al. (2012) Chronic cold stress in mice induces a regulatory phenotype in macrophages: correlation with increased 11b-hydroxysteroid dehydrogenase expression. Brain Behav. Immun. 26, 30–60 70 Sheppe, W.A. and Adams, J.R. (1957) The pathogenic effect of Trypanosoma duttoni in hosts under stress conditions. J. Parasitol. 43, 55–59 71 Arif, A.A. et al. (1999) Antibody response to heat shock proteins and histopathology in mice infected with Trypanosoma cruzi and maintained at elevated temperature. J. Parasitol. 85, 1089–1099 72 Govaerts, M. et al. (1986) Influence of heat stress on experimental Trypanosoma brucei brucei infection in mice. Ann. Soc. Belg. Med. Trop. 66, 161–166
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