Many pathogens, including bacteria influenza virus, and HIV are associated with altered sleep (12
). The sleep regulatory substance Factor S isolated from human urine and rabbit brain was identified as muramyl peptide (54
). The structure of Factor S is similar to the monomeric muramyl peptides found in bacterial peptidoglycan. Subsequent research led to investigations of how pathogen-associated molecular patterns (PAMPs) and their respective pattern recognition receptors (PRRs) alter sleep (12
). Intriguingly, pathogens altering sleep affect many of the same inflammatory cellular pathways, cytokines, and other sleep regulatory substances that waking activity does. It thus appears that the excessive sleep or sleepiness occurring with many infections is the consequence of amplification of physiological sleep regulator mechanisms.
The first description of the effects of a pathogen on sleep over the course of the induced acute phase response involved infecting rabbits with Staphylococcus aureus
). Staphylococcus aureus
infected rabbits exhibit enhanced NREM sleep and less REM sleep. Similar sleep patterns were found with other pathogens including Escherichia coli
and Pasteurella multocida
). However, microbial-mediated sleep effects vary depending upon the species, route of infectious agent entry, time of day of exposure, and prior sleep history. In addition, bacterial cell wall components, such as the endotoxin lipopolysaccharide—a component of the outer membrane of gram-negative bacteria, enhance NREM sleep when injected systemically or centrally. Finally, high doses of heat-killed bacteria also have the capacity to induce sleep and other facets of the acute phase response, thereby suggesting that bacterial replication per se
is not required for bacterial PAMP recognition by PRRs. These effects, like muramyl peptides, are also mediated by cytokines. Sleep alterations induced by these pathogens on their components are quite profound, similar to those sleep responses induced by central or systemic application of IL-1beta or TNF-alpha. Indeed, the IL-1RA and anti-IL-18 attenuate the enhanced NREM sleep induced by muramyl dipeptides indicating that pro-inflammatory cytokines are responsible for bacterial pathogens alteration of sleep.
The host’s acute phase response to influenza viral infection involves many of the same responses induced by bacteria including increased sleep, fever (although mice exposed to influenza have reduced body temperature), and reduced activity (12
). In humans, low titers of influenza only appear to alter sleep and not other acute phase responses. In mice and rabbits, the aforementioned acute phase response characteristics are observed with live but not killed influenza virus. However, the mechanisms for sleep-induced effects of influenza are not fully understood.
Influenza viral challenge is associated with IL-1beta, TNF-alpha, IL-6, and interferon production in the lung and brain and in mice sleep is enhanced for days during the infection (12
). Mice lacking both TNF receptors have attenuated NREM sleep responses to influenza infection compared to mice that have intact receptors suggesting that TNF-signaling is required for the manifestation of the full acute phase response (30
). Further, in response to influenza infection, mice lacking the iNOS gene (iNOS induction is downstream from TNF-alpha activation) have lower NREM sleep responses and greater REM sleep suppression compared to controls (48
). Inflammatory sleep regulatory substances produced/regulated by glia mediate the acute phase sleep response to viral infection. For example, macrophages and microglia have the capacity to produce large amounts of IL-1beta and TNF-alpha in response to viral infection. Moreover, mice lacking macrophage inflammatory protein 1-alpha, which is involved with microglial regulation, do not have the typical dark phase enhanced sleep in response to influenza infection than wild types (57
After intranasal influenza virus challenge, the virus is found in the olfactory bulb and is associated with increased pro-inflammatory cytokine production in the olfactory bulb (58
). The virus is typically not detected in other brain regions such as the somatosensory cortex but has been reported in the hypothalamus (59
). Nevertheless, in mice, the timing of the acute phase responses, including sleep alterations, correlates with virus localization to the lungs. Systemic inflammatory cytokines stimulate afferent vagal nerve inputs to promote sleep (40
). Consequently, it is likely that the observed sleep effects following intranasal influenza inoculation involve inflammatory stimulation of vagal afferents.
One aspect of the immune response to viruses and its interaction with sleep involves antibody responses. For instance, in humans, acute sleep deprivation inhibits hepatitis A vaccine-generated antibodies (60
). Further, a mild amount of sleep loss prior to immunization against influenza reduces immunoglobulin G antibodies to influenza for days, although this antibody titer difference disappears 3 weeks after immunization (61
). Yet, in mice, mild amounts of sleep loss do not alter antibody development against influenza (62
). Nonetheless, antibody protection and acute phase responses may interact to alter one another, although the mechanisms are mediated through different pathways. Thus, sleep alone is an insufficient measurement of influenza pathogenesis.
The effects of sleep loss on the host’s response to influenza remain to be clarified. Prior sleep loss before inoculation is described as being protective while sleep loss following inoculation being detrimental. (63
). Sleep loss alters inflammatory substances and the magnitude and direction of the effects are likely dependent on the activation state of these substances. For instance, the length and type of sleep deprivation, and the time of day affect the ability of inflammatory substances to interact with the host’s response to the virus. In addition, the viral preparations used or the host’s immunological status are likely key elements. Sleep deprivation prior to infection may be protective as similarly found in mice with B16 melanoma or D. melanogaster
with bacteria resistance (66
). Consequently, it is plausible that sleep deprivation under certain circumstances can prime the immune system by altering inflammatory agents or pathways to enhance the immune response to a pathogen.
Viruses, such as HIV, also alter sleep. Sleep complaints and excessive daytime sleepiness, insomnia, and night time awakenings are common in HIV infected individuals (68
). Further, disturbed sleep is magnified in these individuals as the disease progresses. A reduction in EEG slow wave activity is often found in individuals with HIV (69
). However, individuals with HIV that do not show other typical symptoms associated with AIDS have enhanced slow wave sleep before acquired immune deficiency syndrome develops (70
). HIV infects microglia, and individuals with HIV have impaired macrophage and microglial functioning (72
). Thus, impairment in these particular cells is likely to alter sleep regulatory substances which further alter sleep. Indeed, HIV is associated with impaired TNF-alpha release (73
). Consequently, it is likely that individual with HIV have impaired abilities to mount the necessary daily sleep regulatory cytokine responses via microglia leading to their sleep disturbances and reduced EEG slow wave activity.
7.1. Pattern Recognition Receptors
Pathogens, including bacteria, flagellum, viruses, and their components including muramyl dipeptides, LPS, RNA, and DNA are pathogen-associated molecular patterns (PAMPs) (74
). PAMPs are highly conserved molecular components of pathogens. Pathogenic components are recognized by pattern recognition receptors (PRRs) on or within certain cells. PAMPs play a vital role to the identification and processing of pathogens. Enhanced NREM sleep following muramyl dipeptide, LPS, gram negative and gram positive bacteria, viral RNA, and many other pathogens occur through the activation of PAMP receptors (12
). PAMP receptors on the cell surface, endosome or within the cytosol include toll-like receptors (TLRs), and nucleotide binding oligomerization domain-like receptors (74
). Upon PRR activation inflammatory pathways, including NF-kappaB, COX and NOS, activate inflammatory molecules, sleep regulatory substances, and cytokines directly or indirectly. Indeed, increased brain IL-1beta and TNF-alpha occur after viral or bacterial infection; these changes are likely responsible for the sleep responses associated with PRR stimulation. TLRs also activate the inflammasome leading to the activation of IL-1beta and TNF-alpha (see below) (75
As already mentioned bacterial cell wall products such as muramyl peptides or LPS are PAMPs, and they are recognized by PRRs such as TLR2 or TLR4 (74
). In the case of influenza virus, double-stranded (ds) viral RNA is the PAMP. The TLR3 recognizes viral ds RNA. Mice lacking TLR3 infected with mouse adapted influenza virus have reduced NREM sleep, body weight, and hypothermic responses compared to mice that possess that gene (76
). Thus, PRRs are vital to the pathogen-induced sleep response by modulating inflammatory sleep regulatory substances.