Relationship of Infection to Altered Sleep Behavior

Sleep has been proposed as an innate host defense, exerting effects on both specific and nonspecific immunity. One of the most seminal studies dealing with the effects of sleep on immune potential was that from Brown's group showing that depriving influenza virus-immune mice of sleep for 7 h following total respiratory tract viral challenge abrogated antiviral immunity within the lungs and lowered the level of anti-influenza antibody in lung homogenates (Brown 1989). In immune mice nasobronchial immunity to influenza virus reflects the function of secretory IgA (SIgA) within the mucosal mucocilliary blanket, while serum IgG mediates protection within the lung parenchyma. While provocative, unfortunately a follow-up investigation by Renegar et al., attempting to duplicate these studies in immune mice, was unable to abrogate mucosal anti-influenza viral immunity with a single postviral-challenge sleep-deprivation episode (Renegar, Floyd, and Krueger 1998). Furthermore, even one pre- and two postchallenge sleep-deprivation episodes in young adult or old mice, or two prechallenge sleep-deprivation episodes in old mice had no effect on viral immunity in this follow-up study. Sleep deprivation did not depress the level of serum influenza-specific IgG antibodies, and there seemed actually to be an increased influenza-specific serum IgG compared with normally sleeping mice in aged immune mice boosted 3 weeks before challenge and sleep deprived once before and twice after challenge. An independent assessment of effects in the two age groups studied further revealed no evidence for differences in antiviral respiratory immunity between young and old mice.

At this stage then, despite the intense interest generated by Brown's initial observation, it is evident that there is no categorical evidence for an effect of sleep deprivation in this particular model of viral immunity in animals. That having been acknowledged, we note that sickness per se has been taken to refer to a combination of subjective, behavioral and physiological changes that sick individuals exhibit during the course of an infection. Many of these changes are thought to be associated with, and or causally related to, the effects of IL-1 and other proinflammatory cytokines on brain receptors that are essentially identical to those characterized on immune cells (Dantzer 2004). The expression and action of a number of proinflammatory cytokines in the brain in response to peripheral cytokines, as we have already discussed above, are regulated by a number of molecular intermediates including anti-inflammatory cytokines such as IL-10 and IL-1ra, growth factors such as insulin-like growth factor-1 (IGF-1), hormones such as glucocorticoids and neuropeptides, including vasopressin, alpha-melanotropin, substance P, and somatostatin. Other groups have thus addressed whether sleep disruption may impinge on viral resistance secondary to intervening alterations in some of these mediators, and/or whether cytokines produced in response to viral infection may alter sleep physiology.

In one such study, Hermann, Mullington, Hinzeselch, Schreiber, Galanos, and Pollmacher (1998) used endotoxin (associated with bacterially induced inflammatory processes) as a modifier of sleep. Limited host defense activation by endotoxin does not affect daytime sleepiness and NREM sleep in humans. However, the Hermann study investigated the effects of a more intensive stimulation with Salmonella abortus equi endotoxin (0.8 ng/kg), given 12 h following host response priming by GMCSF (300 mu/g, subcutaneously), on daytime sleep and sleepiness in 10 healthy subjects and placebo controls. Endotoxin induced increases in rectal temperature, and in plasma levels of TNF-a, IL-6, IL-1ra, and cortisol. In a nap occurring 1 h following endotoxin administration, total sleep time and NREM sleep stage 2 were reduced, whereas wakefulness and sleep onset latency were increased. After this first nap sleepiness transiently increased, to a peak occurring prior to a second nap, but this nap and the following ones were not influenced by endotoxin. The authors concluded that one cause of daytime sleepiness during infections may be prior sleep disruption and, furthermore, that this kind of sleepiness is not necessarily associated with an increased pressure for further "catch-up" sleep. Mullington et al. also intrigued by data in the animal literature suggesting that in animals at least, activation of host defense mechanisms increases NREM sleep amount and intensity, which is likely to promote the ability of the host immune system to defend itself against challenges from the environment, also explored the effects of various doses of endotoxin on host response, including nocturnal sleep in healthy volunteers (Mullington et al. 2000). If given before nocturnal sleep onset, endotoxin caused a dose-dependent increase in rectal temperature, heart rate, and plasma levels of TNF-a, TNFrs, IL-1ra, IL-6, and cortisol. While the lowest doses increased circulating levels of cytokines and cytokiners, they did not affect rectal temperature, heart rate, or cortisol, but did augment the amount and intensity (delta power) of SWS (stages 3 and 4). In contrast, the highest dose of endotoxin disrupted sleep, further emphasizing the potential complexity of sleep-related changes associated with/caused by, infection.

Additional studies have explored sleep changes in relation to cytokines associated with viral (not bacterial) infections. The effects of two low doses of IFNa (a cytokine produced early following viral infection) on nocturnal sleep was studied in 18 healthy men by means of polysomnographic sleep recordings (Spathschwalbe, Lange, Perras, Fehm, and Born 2000). Subjects were allowed to sleep from 23:00 h to 07:00 h following subcutaneous administration of 1000 to 10,0000 U/kg of recombinant IFNa or placebo at 19:00 h. The higher dose of IFNa suppressed slow wave sleep while increasing time spent in shallow sleep during the first half of sleep time. In addition, REM latency was postponed and the time spent in REM sleep was decreased after IFNa treatment (versus placebo). It should be noted that in contrast to these data in humans, similar studies in animals suggests IFNa has in fact a sleep-promoting effect! Interestingly, despite these studies on virally induced IFNs, and those discussed earlier on other inflammatory cytokines, there is surprisingly little data available concerning the sleep effects of IFNy. Intracerebroventricular injection of human IFNy in rabbits led to dose-dependent increases in NREM sleep, electroencephalographic slow wave activity and brain temperature (Kubota, Majde, Brown, and Krueger 2001). All of these effects were attenuated after heat inactivation of the IFNy. IFNy suppressed REM sleep only if given during the light period, but not when given at dark onset. Interestingly, while a TNFr fragment did not affect sleep parameters when given at dark onset, it attenuated IFNy-induced NREM sleep and the increased brain temperature, consistent with the notion not only that IFNy is involved in sleep responses during infection, but that it may have a synergistic interaction with TNF-a in the process.

Based on data from an interesting study precipitated by work with HIV-positive individuals Hogan et al. have suggested that chemokines, and not (just) cytokines, may be important "players" in the regulation of virally induced changes in sleep physiology (Hogan, Hutton, Smith, and Opp 2001). It is known that sleep is altered early in the course of HIV infection, before the onset of AIDS, consistent with effects of the virus on neural processes. Results from earlier studies had indicated that HIV envelope glycoproteins were potential mediators of those responses. Accordingly, since some CC-chemokine receptors are recognized now to be coreceptors for HIV and to bind HIV envelope glycoproteins, Hogan's study investigated in animal models whether selected CC chemokine ligands altered sleep and whether their mRNAs were detectable in brain regions important for sleep. CCL4/MIP-1P beta, but not CCL5/RANTES, injected intraventricularly into rats prior to dark onset increased non-REM sleep, fragmented sleep and induced fever. Furthermore, they found that mRNA for the chemokine receptor CCR3 was constitutively expressed in multiple brain regions.

Before concluding this section, the reader's attention should be drawn to an interesting study by Morrow et al. evaluating sleep-wake behavior and core body temperature of mice with homologous deletion of the gene encoding IL-6 (IL-6KO) and C57BL/6J control mice after intraperitoneal administration of 10 ^g lipopolysaccharide (LPS) (Morrow and Opp 2005). To assess the additional possible role for a circadian rhythmicity in the feedback mechanisms which regulate responses to immune challenge responses to LPS were measured after administration of LPS at the beginning of both the light and dark portions of the light:dark cycle. LPS-induced increases in NREM sleep of both IL-6KO and control mice, but the increase was less pronounced in the KO mice than in the wild-type controls. The greatest differences in LPS-induced increases in NREM sleep were observed when LPS was given after light-onset (increase over vehicle for controls: 23±0.5%; for IL-6 KO mice 4.1±0.5%). For both IL-6KO and controls REM sleep was suppressed to the same extent after LPS, regardless of the timing of administration. In addition to the sleep-related changes, LPS-induced a febrile response in wild-type mice regardless of time of administration (~1.6°C), while in contrast, the same doses of LPS-induced hypothermia in the IL-6 KO mice (ranging from declines of 5 to 2.2°C depending upon administration after dark versus light onset respectively. Clearly based on these data, bacterial infection per se can potentially have profound effects on sleep behavior (and core body temperature) in rodents, which may not be seen in man.

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