Cytokine Induced Sickness Behavior Evolved Defense Infectious Pathogens Biology Essay

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Western biomedicine and evolutionary science represent two distinct models of viewing and analyzing health and disease among the human species. For a time, both domains existed mutually exclusive. Western biomedicine has been the mainstay in treating ill patients by trained doctors and physicians through institutions like hospitals and clinics. Evolutionary science supplements our understanding of the human race through genetics research and theory testing in laboratories. However, with the advent of Darwinian Medicine (evolutionary medicine) we have witnessed a breakthrough in our understanding of sickness and disease in the application of evolutionary principles to medical knowledge. Darwinian Medicine examines the biochemical/anatomical (proximate) and evolutionary (ultimate) causes of disease and sickness. Though medical schools tend to overlook the importance of teaching evolutionary medicine when instructing future doctors, we can still gain insight into treatment options and maintaining a healthy society by viewing disease through the scope of our evolved bodies.

Sickness Behavior Syndrome is induced by acute infection; it is a set of behavioral changes occurring in a sick host. Sickness Behavior is commonly diagnosed as directly resulting from a pathogen's effect on the host. However, this common view of Sickness Behavior is a misconception because it implies that the change in host behavior is advantageous for the pathogen. Though Sickness Behavior is localized to those that have acute infection, it is not the pathogen (virus) or bacteria that directly cause the change in behavior. In actuality, Sickness Behavior is activated by the host immune system in the presence of infection. Behavioral changes brought about by the immune system response commonly include "…a loss of interest in usual activities, lethargy, anorexia," a change in sleep cycle resulting an increase in sleep duration, and an increased sensitivity to pain also known as hyperalgesia (Mingam et. al, 2008, p. 1877). A similar definition of Sickness Behavior includes "decreased food intake (anorexia) and pain sensitivity, reticence to engage in pleasurable activities, and reductions in motivated behaviours" (Martin II et. al, 2008, p. 68). I argue that Sickness Behavior and the behavioral changes in the host is an evolved defense against pathogen parasitism that ultimately benefits the host rather than the pathogen. Furthermore, this shift in behaviors increases the chances of the host surviving a pathogen. Overall, Sickness Behavior suits the body for combat against a pathogen and reduces time spent ill.

Sickness Behavior Syndrome can be better understood through the scope of Darwinian Medicine by examining the proximate cause and the ultimate cause. The proximate cause is the description of the bio-chemical pathway that causes Sickness Behavior. Basically, the proximate cause explains what is going on inside the body of the host, on a chemical and molecular level, that leads to Sickness Behavior. On the other hand, the ultimate cause deals with the evolutionary explanation of the behavior. The ultimate cause looks at why such a behavior would be favored by the forces of natural selection. Natural selection is a key mechanism by which evolution occurs; it is a process by which a trait becomes more or less common in a given population due to its benefits or costs on the survival of an organism. Accounting for the ultimate causation of Sickness Behavior can lead to a greater understanding of evolved defenses in the human body.

The proximate explanation of Sickness Behavior investigates the chemical actors on the molecular stage of the host's body. The story begins with the pathogen. A pathogen is an "infectious organism…[like] bacteria (such as staph), viruses (such as HIV), and fungi (such as yeast)" ("Definition of Pathogen", n.d.). Many pathogens work like a parasite in that it depends on the host for survival and reproduction; in addition, pathogens may also use the host as a vehicle for transfer to other hosts. A common example is that of the influenza virus (flu). There are many variations of the flu virus but most generally produce similar symptoms in the host; two evolved symptoms that support greater host to host transfer of the flu virus is coughing and runny nose. In this situation, coughing and runny nose expel the pathogen outward into the environment where they can lay dormant for sometime until another host comes upon them and inadvertently introduces the pathogen into his body.

The immune system is "a network of cells, tissues, and organs that work to defend the body against…bacteria, parasites, and fungi" ("Immune System", 2010). When a pathogen enters the body the immune system is activated to respond. First, the immune system must know that a pathogen has entered the body; to do this, the immune system recognizes pathogen-associated molecular patterns (PAMPs) generated by bacteria and fungi (Kelley et. al, 2003, p. S113). For example, gram-negative bacteria are characterized by an outer membrane consisting of lipopolysaccharides (LPS); LPS are fatty molecules that functions as a protective coating around gram-negative bacteria. LPS serves as a PAMP, or marker, allowing for identification of pathogen by the immune system (Kelley et. al, 2003, p. S113). The introduction of LPS into the blood stream is a simple and popular method of inducing sickness behavior in animals. However, Sickness Behavior can be elicited by other pathways involving the immune system; generally, the activation of immune system cells in response to a foreign invader can lead to Sickness Behavior (Bluthe et. al, 2000, p. 4448). Once aware of a pathogen, the immune system can respond in many different ways in order to eliminate the foreign substance; the response concerning Sickness Behavior is the production of cytokines IL-1, IL-6, and TNF (Mingam et. al, 2008, p. 1877).

Cytokines are "small proteins that have a specific effect on the interactions, communications, and behavior between cells" ("Definition of Cytokine", 1999). Cytokine IL-1 and IL-6 administration via injection has led to empirical observations of "…lethargy, weakness, malaise, listlessness, inability to concentrate, fatigue, anorexia, sleep changes and fever" (Kelley et. al, 2003, p. S113). The LPS causes the production and release of cytokines by macrophages and monocytes; macrophages and monocytes are components of the immune system that respond to harmful microorganisms (Kelley et. al, 2003, p. S113)(Dantzer, 2002, p. 223). Cytokines come in various flavors, but the type produced by the immune system during the acute phase reaction to infection associated with Sickness Behavior are interleukins (IL-1 & IL-6) and tumor necrosis factor (TNF) (Mingam et. al, 2008, p. 1878). Interleukins are proteins that "regulate cell growth, differentiation, and motility…[by] [traveling] to [a] target cell and [binding] to it via a receptor molecule on the cell's surface…[triggering] a cascade of signals within the target cell that ultimately alter the cell's behaviour" ("Interleukin", n.d.).

Cytokines IL-1 and IL-6 journey to the brain all while TNF plays an important chemical role in synthesizing more cytokines (Dantzer et. al, 2008, p. 160). IL-1 and IL-6 affect the brain by sending dual signals; one message gets to the brain almost immediately and another message takes sometime to reach the brain. A simplified way to conceptualize the different signals is to think of using the telephone (fast) versus using standard mail (slow) to relay a message. The speedy message is transferred across neurons. Neurons near the area of inflammatory cytokine release inform the brain that cytokines in the body have been produced in response to a pathogen (Dantzer, 2002, p. 223). This message leads the brain to produce cytokines in the hypothalamus which functions to control internal body temperature, hunger, tiredness, and sleep (Dantzer, 2002, p. 224). The much slower message reaches the brain through cytokine diffusion. Cytokine diffusion is the journey from the area of cytokine release to the brain via the blood stream; this process is regulated by the rate of blood flow (Dantzer et. al, 2002, p. 224). Cytokines enter the region of the brain when the blood carrying the cytokines reaches the circumventricular organs (CVOs) surrounding the brain; the circumventricular organs control the uptake of blood to the brain. CVOs are located around the ventricles of the brain and have contact with both blood and spinal fluid (Johnson et. al, 1993, p. 679). Once in the brain, the cytokines in the blood make their way to the hypothalamus and amygdaloid complex where their journey ends and behavioral change is signaled (Dantzer, 2002, p. 223).

Once a threshold cytokine level is achieved in the brain, a reorganization of priorities leads to behavioral changes in the host. This reorganization is regulated by the immune system and the new motivated behaviors "are not the result of weakness and physical debilitation that accompany an infectious illness [but]…support the metabolic and physiologic changes that occur in the infected organism and increases [its'] efficiency" (Dantzer et. al, 2008, p. 132). The ultimate explanation of Sickness Behavior makes use of an adaptive understanding of the behavioral changes mentioned earlier: 1) decreased appetite, 2) increased amount of sleep, and 3) hyperalgesia.

According to Nesse and Williams, an evolved defense "…is a coordinated defense shaped by natural selection and activated when specialized sensors detect cues that indicate the presence of a specific threat" (Nesse & Williams, p. 8). The "specialized sensors" in Sickness Behavior are part of the immune system which "detects cues," or PAMPs, when a threatening pathogen is noticed. In order for Sickness Behavior to be considered an evolved defense, it must be adaptive and benefit the host in order to ultimately increase fitness (reproductive success). Hence, the behavioral changes that occur in Sickness Behavior must produce an overall adaptive benefit to the host.

It is important to distinguish natural selection from natural perfection. In no way does natural selection, the main force by which evolution occurs, work in order to produce a perfect specimen in the population. Natural selection balances costs and benefits to produce trade-offs that will be adaptive for an organism in a specific environment. Therefore, it is appropriate to understand Sickness Behavior as a balance between costs and benefits. Sickness Behavior is studied in many mammals such as pigs, monkeys, and rodents in controlled settings and in the wild. Studies examining animals far exceed studies examining humans; however, a growing trend in examining human subjects in the field of Sickness Behavior is leading to increased acknowledgement of the need for human testing (Vollmer-Conna, 2004, p. 1294). Though the majority of human subjects represent a small percentage of variation, their participation is expanding the possibility for multi-cultural and trans-demographic human studies of Sickness Behavior.

From an epidemiological standpoint, Sickness Behavior tends to have a higher prevalence among individuals with chronic disease such as diabetes and cancer. This pattern can be explained by taking another look at the proximate mechanisms involved in Sickness Behavior. Cytokines, the messenger and inevitable behavior changing molecules involved in Sickness Behavior, are secreted in various forms of sickness; an immune system that responds readily to chronic disease is therefore flooding the brain with cytokine activity. Cytokines IL-1 and IL-6 accompany immune response to "…chronic fatigue syndrome (CFS) and chronic infections" (Dantzer, 2002, p. 229). Applying this logic, prevalence of chronic infections can lead to a greater prevalence of Sickness Behavior. Chronic infections are generally more prevalent in societies that have a longer expectancy of life and foster an environment that is mismatched relative to evolved human bodies. The United States is an example of such a society as the leading cause of death is chronic disease (CDC, n.d.). Individuals susceptible to chronic diseases such as diabetes and heart disease - with overactive cytokine presence - are also susceptible to Sickness Behavior. New research has linked the onset of depression, a mental disorder that plagues an individual with low mood and enthusiasm, with cytokine over-activation in Sickness Behavior (Weary et al, 2008, p. 772). Finally, more cases of Sickness Behavior have been observed in older populations than adult and adolescent populations; however, this observation can be explained by a greater prevalence of chronic disease among the older population (Kelly et al., 2003, p. S114).

Sickness Behavior appears to have a strong evolutionary history. Sickness Behavior has been induced in mice through lipopolysaccharide (LPS) injection and in pigs administered via food (Martin II et al, 2008, p. 70)(Johnson et al., 1994, p. 310). Studies centralized around the induction of fever in controlled lab animals have also described behavioral changes congruent to Sickness Behavior (Martin II et al, 2008, p. 72-75). Animals in the wild such as monkeys, fish, and calves have been observed to have motivated Sickness Behavior caused by an infectious agent or pathogen (Weary et al., 2008, p. 771).

Decreased Appetite

Cytokines, such as IL-1, have been traced to the reduction of appetite and motivation to eat (Weary et. al, 2008, p. 772). The reduction of appetite is a great example of an evolutionary trade-off in Sickness Behavior. With less food ingestion, the host is depriving his body of nutrients and calories that provide the energy needed to perform highly metabolic functions in order to fight off an infection. This is a straightforward cost and can be empirically measured by caloric intake prior to sickness, during sickness, and after sickness. Less food means less energy, forcing the body to prioritize expenditure in a life or death situation. However, ingesting less food has some surprising advantages. A lowered appetite and less food decreases the chance of ingesting more pathogens and iron and "…helps promote recovery" (Weary et al, 2008, p. 772). It is obvious that introducing more pathogens through food would be detrimental to the host, but the avoidance of iron is not so obviously beneficial. Iron can intensify infectious disease (Kontoghiorghes et. al, 2010, p. 227). Being wary of iron during illness is important because iron fuels bacterial reproduction; most bacteria cannot survive without obtaining iron from the environment, the body of the host (Marcela et al., 2003, p. 1485). Iron is essential for bacteria to perform DNA replication and other vital functions (Marcela et al, 2003, p. 1485). Therefore, by withholding food, the host leads the body to become a more inhosptiable environment for bacteria/pathogens.

It is difficult to test this adaptive theory on humans due to ethical considerations and the dilemma of consenting to infection. However, rats are good model organisms to test this theory because they share many analogous genes with humans ("Human Genome Program", n.d.). In an experiment performed by Murray and Murray in 1979, mice eating patterns were observed in mice infected with bacteria (Listeria monocytogens). Some mice were allowed to eat food freely, leaving the decision making up to the mouse itself, and some mice were force-fed the same amount of food as non-infected healthy control mice. The results implied an adaptive advantage to decreased appetite; "Infected mice that were allowed to regulate their own intake ate only 58% as much as the controls and were much more likely to survive than mice that were force-fed" (Weary et al, 2008, p. 772). The study concluded that reduced appetite and weight loss were positively correlated with survival (Weary et al., 2008, p. 772).

A study conducted by Adamo (2010) and colleagues controlled food intake in crickets infected with a lethal dose of bacteria (p. 4). The crickets were split up into four groups of varying food treatments consisting of a high sugar diet, a high fat diet, no food, and a control diet (Adamo et. al, 2010, p. 5). Crickets treated with a high fat diet had a significantly higher mortality rate than the crickets that were starved (Adamo et. al, 2010, p. 7). Crickets that were starved also had a significantly lower mortality rate than the control crickets given a regular diet (Adamo et. al, 2010, p. 7). Furthermore, Adamo (2010) and colleagues believe that sickness induced anorexia serves to reduce competition over energy between the immune system and metabolic functioning (p. 7).

In addition, a study examining cows infected through LPS infusion that were allowed to self-regulate food intake found the animals healed and returned to normal milk yield quicker than the control force fed cows; observations like this have led biologists and ecologists coupled with economists to lobby for self-regulation of food intake in food animals in order to increase their chance of survival and overall yield (Waldron et al, 2006, p. 605). When deciding farming policy, the consideration of allowing food animals (such as pigs and cows) to self-regulate food intake reflects an understanding of an evolved defense favoring reduced appetite to combat against pathogenic infection.

Increase in Sleep

IL-1 (interleukin-1), a cytokine highly involved in Sickness Behavior mentioned earlier, induces sleep (Johnson et al., 1994, p. 312). Specifically, IL-1 has been shown to induce slow-wave sleep (Johnson et al., 1994, p. 312). Slow-wave sleep can be considered "deep sleep" and is observable in many species in the animal kingdom ("Manual for Sleep Scoring", n.d.). Sleep is important for a variety of reasons; sleep is good for "…energy conservation/protection against energetic exhaustion, thermoregulation, adaptation to [the] [environment], restoration of tissular integrity, and neuronal plasticity" (Maquet et al., 1997, p. 2808). Sleeping is beneficial to the infected host because it induces adaptive behavior listed above. An increase in sleep during infection

Energy conservation is pivotal when fighting off an infection. Coupled with a reduction in appetite from Sickness Behavior, the body finds itself in a state of low fuel supply. Less overall energy requires the body to prioritize avenues of expenditure more strictly such as deciding whether to hunt for food or fight for dominance (Cohn et al., 2008, p. 118). Note that though humans in industrialized societies no longer share the same lifestyle as their hunter-gatherer ancestors, they are still an evolutionary product of that time. Inducing a longer sleep cycle is an adaptive advantage because it curtails energy expenditure for a relatively large amount of time. It is the greatest prioritization of energy expenditure. Furthermore, restoring tissue that was damaged by infection as well as maintaining normal neuron functioning during sleep is all in an effort to get the host back to normal functioning, or homeostasis. Homeostasis is marked by a stable state of equilibrium or balance optimal for reproductive functioning (Bourguignon et al., 2010, p. 118). Normal functioning allows for greater overall fitness. Logically, a mechanism that promotes sleep which serves to maintain homeostasis and consequently increase fitness is a strong candidate for an adaptation.

A retrospective study/analysis that exemplifies the importance of sleep for biological health deals with varying sleep patterns of rabbits infected with bacteria or fungi. A group of scientists studied data that was originally derived from a longitudinal study of sleep alterations in infected rabbits (Imeri & Opp, 2009, p. 206). The group calculated a sleep quality score reflecting sleep duration and intensity of sleep that was correlated with the dosage of pathogen introduced in the rabbits (Imeri & Opp, 2009, p. 206). In the rabbits that received the same infectious dosage, those that survived had a higher sleep-quality score, and therefore received more sleep, than those that died (Imeri & Opp, 2009, p. 206).

A study conducted at the University of California, San Diego, analyzed the correlation between sleep deprivation and normal immune system functioning ("Tufts University," p. 3). 42 men that were deprived of sleep displayed a reduction in immune capabilities the next day compared to a control group ("Tufts University," p. 3). The immune cells responsible for fighting viral infection significantly decreased in number and functioning; the probability of becoming sick greatly increases when not enough sleep is obtained ("Tufts University," p. 3). In addition, increased sleep promotes greater thermoregulation and induction of fever during sickness (Everson, 1993, p. R1152). Inducing an effective fever helps a host defend against infection and reduces the amount of time spent sick; increased sleep can function synergistically with fever by allowing for greater allocation of energy in maintaining a higher body temperature (Blatteis, 1986, p. 111).

It is important to acknowledge that increased sleep is also accompanied by anorexia in Sickness Behavior. The infected host, whilst limiting food intake, may be able to counteract the loss of energy from anorexia by increasing sleep. More time spent asleep frees up the energy that would be used during normal activities such as foraging, moving, and working. By means of dormancy, sleeping rules out the possibility of experiencing added stress from the environment that can further harm the host or require greater energy expenditure. Increased sleeping can be translated to a turtle retracting into its shell when confronted with danger. Aside from regulating normal immune function, increased sleep protects the host from wasting energy and accidentally increasing the risk of his mortality by interacting with stressors in the environment.

Hyperalgesia: Greater Sensitivity to Pain

Among the various messages IL-1 and IL-6 relay, the cytokines signal the brain to activate a pathway, which inevitably calls forth microglia action, centralized in the spinal cord (dorsal horn) (Watkins & Maier, 1999, p. 7712). Microglia are the immune cells of the spinal chord functioning as a support and defense of the central nervous system (Kreutzberg, 1995, p. 357). Of their many functions, the microglia release substances that excite the nerves throughout the body thereby producing a greater sensitivity to pain (Hyperalgesia) (Watkins & Maier, 1999, p. 7712). Research has indicated that this function is not a side effect or byproduct of another function but rather a mechanism evolved for this purpose (Willemen et. al, 2010, p. 554).

The feeling of pain signals pressing danger or bodily harm. Pain is unique in that it generally increases with greater damage and severity; pain cannot be ignored. From the perspective of maintaining fitness of an organism, it is "…essential for the organism that a painful stimulus should become ever more pressing until the subject takes some action to remove its cause" (Zhang et al., 2006, p. 491). However, like decreased appetite, pain represents a trade-off between costs and benefits to the host. Though pain is meant to work like an alarm to avoid further bodily injury, sever cases can cause immobilization (Zhang et al., 2006, p. 491). For example, in a situation where extreme pain is present such as in a hernia or kidney stone, the only action a person can take is to remain still in order to abate the pain. This lack of action has a negative effect on survival let alone a debilitating force on "…emotional [and] economic well being in a human" (Zhang et al., 2006, p. 491).

Better than feeling no pain, Hyperalgesia is an adaptively tweaked alarm that comprises the evolved defensive properties of Sickness Behavior. Hyperalgesia factors in as a highly sensitized alarm for the host. High sensitivity leads the host to shy away from situations that may normally not be as painful. This is important for the survival of the host because it indirectly regulates risky behavior by introducing opposing physical motivation; "…pain enhancement in response to acute tissue inflammation/injury is adaptive" (Watkins & Maier, 1999, p. 149). With an existing injury or infection, an organism is most likely to reduce further damage by reducing the opportunity for further damage. In addition, increased pain notifies the host to attend to an injury or infection (Feldman, 2003, p. 233). If an organism is not aware of the severity of an infection, Hyperalgesia can provide a marker for reprioritization of behavior.

Hyperalgesia is also a means of learning. A study of response to Hyperalgesia in rats conducted by McNally and Westbrook (1998) demonstrated that behavioral learning is correlated with experiences of increased pain (p. 976). Rats that were given an option of eating normal food and food containing neuro-chemicals that induced Hyperalgesia delineated consumption of the latter over time (McNally and Westbrook, 1998, p. 975). In this fashion, Hyperalgesia can teach an organism to avoid behavior that can be deleterious to survival.

Furthermore, Hyperalgesia motivates the host to avoid dangerous behavior and seek homeostasis. In weighing the costs and benefits of pain, it is important to account for the lifestyle of mammalian ancestors and hunter-gatherers. The ancient environment was full of incidences of danger and harm; an organism could become injured hunting for food or open a wound and introduce new infectious pathogens in the process of foraging. Hence, with regards to the environment that Sickness Behavior evolved in, Hyperalgesia as a neuro-immunological response promotes safer self-regulation and awareness.

Areas of Debate

Sickness Behavior is associated with fever in acute phase response via cytokine involvement originating from the immune system. Fever is a highly regulated response by the immune system that serves as an evolved defense against infection (Nesse & Williams, p. 27). Sickness Behavior is believed to be a response regulated by the immune system but there is still debate over the adaptive properties of some of the symptoms. Behavioral changes such as 1) reduced appetite, 2) increase in sleep duration, 3) and Hyperalgesia have direct benefits to a host. However, loss of interest in usual activities has not been shown to provide any direct advantage to a host; though it may reduce energy expenditure, this symptom does not reflect a greater prioritization of maintaining energy.

In addition, current studies examining survival rates among mammals and vertebrate base their conclusive information on correlations. But, a critical scientist recognizes that correlation does not imply causation. Model organisms such as rats, cows, and rabbits are used as test subjects because they share a considerable amount of DNA and life systems functioning with humans. However, we can never be fully satisfied with findings, no matter how remarkable, unless a similar finding is found in humans.

Finally, Sickness Behavior may possibly be a vestigial adaptation of human evolutionary past, an evolutionary legacy. Sickness Behavior may be a mechanism shaped by thousands of years of evolution in an environment where it was once adaptive but now is inefficacious or even maladaptive. Avoiding dangerous pathogens and intake of iron in food is not a major problem for modern humans; due to institutions like the FDA and EPA, most people can rest assured that their store bought food is pathogen free. Furthermore, food labels educate the consumer and allow for an easier means of avoiding foods high in iron. The environment populated by humans today no longer consists of the lethal interactions between pathogens and animals that once defined the environment of the past. Public health measures fight to reduce pathogenic variability in the environment. Staples of technology such as cars and public transportation curtail the use of energy in obtaining food and other needs in the environment. Cultural evolution works at a much faster rate than biological evolution; industrialized countries have structured hospitals and other forums of medical care that provide a greater defense against pathogens. Future studies should strive to analyze Sickness Behavior in an environment that it may be adaptive, such as that of hunter-gatherers. Perhaps through the advent of medical anthropology, Sickness Behavior can be understood more deeply as it is applied in different types of cultures and societies.

For some time Sickness Behavior was thought of as a common set of symptoms of many infections and sicknesses. Research within the past 30 years has changed this perception with the discovery of highly regulated cytokine involvement during periods of infection (Dantzer, 2002, p. 223). Cytokines act as immuno-steroids that relay important messages to the brain in the acute phase response to infection. Interleukin-1 (IL-1), Interleukin-6 (IL-6), and tumor necrosis factor (TNF) are the main players in cytokine mediated Sickness Behavior. Within the brain, the hypothalamus and amygdaloid complex contribute to changes in the body such as 1) reduced appetite, 2) increase in sleep, and 3) Hyperalgesia (increased sensitivity to pain) (Dantzer, 2002, p. 223). These changes have adaptive qualities that better suit hosts for infection and increase rates of survival as observed in mammal test subjects. To fully test the adaptive function of Sickness Behavior, we must look at the effects of each symptom in a specific environment as well as holistically as a collection of trade-offs. By applying the tenets of Darwinian Medicine to the behavioral changes in Sickness Behavior, we can better understand the evolutionary mechanisms and defenses inherent in this common syndrome.