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of severe infection and a greater probability of survival. Muramyl dipeptides (the
monomeric subunits of peptidoglycan that make up bacterial cell walls), endotoxin,
and bacterial LPS can stimulate IL-1 release, which in turn produces somnolence.
Plasma IL-1 concentrations reach a peak at the onset of slow-wave sleep in healthy
individuals [27] , and cerebrospinal fluid (CSF) concentrations of IL-1 increase dur-
ing sleep [28] . TNF- and IFN may also have somnogenic actions, although IL-2,
IL-6, and TNF- do not [22] . Failure to sleep during infection is associated with an
increased severity of clinical signs and a poorer prognosis. Accordingly, animals that
are chronically sleep-deprived tend to have a greater incidence of bacterial infection.
12.2.3 Cytokines and Ingestive Behavior
Loss of appetite during infection may seem to be maladaptive; it appears illogical
that appetite should decrease at a time when the body is expending energy to increase
body temperature. However, loss of appetite in infection is, in the short term, an adap-
tive behavioral response, although in the long term it may lead to malnutrition and
excessive weight loss. In the wild, an animal must expend energy to obtain food, and
in these circumstances loss of appetite allows the animal to conserve its energy,
which is required to mount a fever and fight off infection. By remaining relatively
immobile, an animal is able to curl up and conserve heat, which would otherwise
be lost by convection. Finally, by not foraging an animal is less likely to encounter
predators at a time when it is least able to defend itself.
The decrease in food intake may also facilitate decreases in the plasma concentra-
tions of substances such as iron, which are important for bacterial growth. It is com-
monly believed that malnutrition compromises the immune system, but a controlled
study, in which subjects underwent a loss of 20% of their original body weight over
a 24-week period, found that these individuals did not exhibit an increased inci-
dence or severity of infection (e.g., respiratory infection) compared with controls.
Also, various reports from places where individuals may have been suffering from
malnutrition, such as prisons, showed that the most malnourished individuals suc-
cumbed to fewer infections than their well-fed counterparts [29] . Studies in endo-
toxin-treated mice showed that those animals demonstrating the greatest degree of
anorexia and weight loss in response to the infection were the least likely to die.
Conversely, normalizing the caloric intake of infected animals by intragastric feed-
ing actually increased mortality, with 93% of force-fed animals dying, compared
with 43% given the same dose of LPS but allowed to regulate their own food intake.
Central or peripheral administration of pro-inflammatory cytokines also reduces
feeding, suggesting that these cytokines may play a role in anorexia. Bacterial LPS
and IL-1 reduce operant food intake, a measure of food-seeking behavior. TNF-
knockout mice have normal circadian variations in food intake and body weight gain
and develop obesity following the administration of a high-fat or high-calorie diet.
In contrast, mice that overexpress TNF- exhibited wasting and chronic inflamma-
tion, suggesting that this cytokine affects feeding during pathological conditions.
Interferon therapy for chronic conditions such as cancer and multiple sclerosis is
associated with a reduction in appetite and progressive weight loss. The effect of
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