Reduced feed intake, inactivity, sleep and decreased social interaction are behavioral states observed in animals with an acute bacterial or viral infection. These nonspecific behavioral responses are known collectively as sickness behavior, and in association with other acute-phase responses, are critical for maintaining homeostasis during infection. Because the immune system has the critical responsibility of contending against pathogens and the brain ultimately controls behavior, the presentation of sickness behavior suggests that the immune system and brain communicate. The nature of this communication system has been the subject of intense investigation and it is now evident that the immune system shapes the activity of other systems including the brain by secreting hormone-like molecules called cytokines.
Overwhelming evidence now indicates that pathogens induce sickness behavior by stimulating leukocytes to produce soluble proteins called cytokines (Dantzer and Kelley, 1989; Kent et al., 1992). In essence, the immune system uses cytokines such as interleukin (IL)-1b, IL-6, and tumor necrosis factor a (TNFa), to convey information to the brain about the level of immunological activity. Indeed, it has been shown that if macrophages are unable to produce cytokines when exposed to inflammatory stimuli (e.g., lipopolysaccharide), the immune system cannot communicate with other systems and animals do not behave sick as they would otherwise (Segreti et al., 1997). Thus, when animals are subjected to pathogens, the production of cytokines is the first step towards the induction of sickness behavior.
Our understanding of the interactions between the brain and the immune system has increased dramatically in the ten years since Hart published his treatise describing the biological basis for sickness behavior (Hart, 1988). The important argument made by Hart was that the behavior patterns of sick animals are not maladaptive responses or the effect of debilitation, but rather organized evolved strategies that facilitate recovery. A clever set of experiments conducted in the 1970's that investigated fever in the lizard Dipsosaurus doralis provides an excellent example of the importance of "behaving sick" (Vaughn et al., 1974). Like all ectotherms, lizards regulate body temperature by behavioral thermoregulation. Thus, when placed in an experimental chamber where one end was kept at 50o C (a lethal temperature) and the other end at 30oC, lizards regulated body temperature by shuttling from one end to the other. The body temperature at which lizards moved from the hot end to the cooler end represented the high set-point, and the body temperature at which lizards moved from the cooler end to the hot end represented the low set-point. Interestingly, lizards challenged with killed bacteria had a higher high set-point temperature and a higher low set-point temperature than controls. Thus, immune-challenged lizards "chose" to develop a fever, which was behaviorally mediated. The importance of the behavioral response was later revealed when lizards were inoculated with live bacteria, but kept at a constant 34, 36, 38, 40, or 42o C so as to prevent behavioral thermoregulation. The results showed a high positive correlation between body temperature (i.e., environmental temperature) and survival (Kluger et al., 1975).
There also is some evidence that the loss of appetite in sick animals is an adaptive response. Murray and Murray (1979) experimentally infected mice with Listeria monocytogenes (LD50) and let some consume food ad libitum, while others were intubated and force fed to the level of free-feeding, non-infected controls. Mice allowed to consume food ad libitum ate 58% of the controls and were much more likely to survive than those force-fed. Furthermore, there was a positive relationship between weight loss and survival for the infected mice with ad libitum access to food. Therefore, survival appears to be positively related to anorexia and weight loss, at least in the short term. Of course, when anorexia and weight loss caused by degradation of body protein and fat persists, a condition known as cachexia or wasting develops. A positive relationship between loss of lean body mass and mortality in a number of diseases has been reported.
Evidence indicating that decreased feed intake in response to disease challenge is adaptive in growing domestic food animals is indirect, but important nonetheless. Pigs kept under management schemes that limit host-pathogen interactions consume more feed, grow faster and retain more nitrogen for proteineous tissue growth, compared to those maintained in a dirty, less hygienic environment (Williams et al., 1997a,b,c). Under the latter circumstance, a common practice is to increase dietary lysine to account for the decreased intake caused by disease challenge. The idea is that lysine intake may limit protein accretion in immune challenged pigs. The evidence is mounting, however, that stress-related decreases in feed intake are associated with a lower lean growth potential (Baker, 1996; Webel et al., 1997). Results in pigs and chicks indicate that stimulation of the immune system reduces the capacity for lean tissue accretion (Williams et al., 1997a,b,c; Webel et al., 1998). Therefore, the practice of increasing lysine to account for lower feed intake in sick or immune challenged animals appears to be invalid (see Baker, 1996). In retrospect, it is logical for an animal to adjust its feed intake according to the balance between anabolic and catabolic processes.
These examples underscore the importance of understanding the complex behavioral and metabolic responses triggered by immune cells in response to pathogens. Animals have always lived surrounded by pathogenic microorganisms and will continue to do so regardless of the animal housing system. Therefore, effective disease management will continue to be one of the most important aspects of animal production. Management practices that enhance the host response, and not thwart it are needed. Clearly, disease reduces animal well being, and increased incidence of disease may indicate other problems in the environment that threaten good well-being. It is important to improve animal well being by minimizing the incidence of disease, reducing the severity of disease, and/or enhancing recovery from disease. Because behavior is an important part of the host response to infection, a better understanding of sickness behavior should help improve animal well-being in the face of disease.
Literature Cited
Baker DH (1996) Advances in amino acid nutrition and metabolism of swine and poultry. In: Nutrient Management of Food Animals to Enhance and Protect the Environment, Kornegay ET (ed). Lewis Publishers, Boca Raton, Florida, p. 41-53.
Dantzer R, Kelley KW (1989) Stress and immunity: An integrated view of the relationships between the brain and the immune system. Life Sci. 44:1995-2008.
Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12:123-137.
Kent S, Bluth� RM, Kelley KW, Dantzer R (1992) Sickness behavior as a new target for drug development. Trends Pharmacol. Sci. 131:24-28.
Kluger MJ, Ringler DH, Anver MR (1975) Fever and survival. Science 188:166-168.
Murray MJ, Murray AB (1979) Anorexia of infection as a mechanism of host defense. Am. J. Clin. Nutr. 32:593-596.
Segreti J, Gheusi G, Dantzer R, Kelley KW, Johnson RW (1997) Defect in interleukin-1 secretion prevents sickness behavior in C3H/HeJ mice. Physiol. Behav. 61:873-878.
Vaughn LK, Bernheim HA, Kluger MJ (1974) Fever in the lizard Dipsosaurus dorsalis. Science 252:473-474.
Webel DM, Finck BN, Baker DH, Johnson RW (1997) Time course of elevated plasma cytokines, cortisol and urea-nitrogen in pigs following intraperitoneal injection of lipopolysaccharide. J. Anim. Sci. 75:1514-1520.
Webel DM, Johnson RW, Baker DH (1998) Lipopolysaccharide-induced reductions in food intake do not decrease the efficiency of lysine and threonine utilization for protein accretion. J. Nutr. 128:1760-1766.
Williams NH, Stahly TS, Zimmerman DR (1997) Effect of chronic immune system activation on the rate, efficiency, and composition of growth and lysine needs of pigs fed from 6 to 27 kg. J. Anim. Sci. 75:2463-2471.
Williams NH, Stahly TS, Zimmerman DR (1997) Effect of chronic immune system activation on body nitrogen retention, partial efficiency of lysine utilization, and lysine needs of pigs. J. Anim. Sci. 75:2472-2480.
Williams NH, Stahly TS, Zimmerman DR (1997) Effect of level of chronic immune system activation on the growth and dietary lysine needs of pigs fed from 6 to 112 kg. J. Anim. Sci. 75:2481-2496.
|
