Sleep and infections

The human body is constantly exposed to the attacks of pathogens which can trigger acute or chronic infections. When this occurs, the general common feeling is a need to sleep. Such somnolence is a component of the so-called sickness syndrome or sickness behavior, which facilitates recovery. However, changes in the sleep-wake pattern may show distinct features during different infections. Marked changes in the sleep-wake pattern, including narcolepsy-like neurophysiological alterations, have been observed following infection with the parasites African trypanosomes. Interestingly, infection with influenza virus has been recently associated with narcolepsy as well. In this doctoral thesis, rodent models of H1N1 influenza A virus infection and African trypanosomiasis were used to investigate the sleep-wake pattern, related neural circuitry and inflammatory mediators. The first investigation (which has been published) was focused on influenza infection. In particular, Rag1-/- mice, which lack adaptive immunity, were used to verify whether a mouse-neuroadapted influenza A virus (A/WSN/33) could cause per se narcoleptic-like changes following intranasal instillation. In the normal sleep structure, rapid eye movement (REM) sleep is preceded by NREM sleep in cyclic sequences. During the fourth we postinfection, a fragmented sleep-wake pattern and alterations of the NREM-REM sleep sequence, with the occurrence of so-called sleep-onset REM (SOREM) episodes, were observed in the murine model of influenza infection. In SOREM episodes, REM sleep is preceded by wake and therefore the NREM-REM sleep sequence is disrupted. Interestingly, immunohistochemistry for A/WSN/33 virus antigens showed in the infected mice hypothalamic and upper brainstem localization, which included subsets of sleep-wake-regulatory neurons. Moreover, upregulation of transcripts encoding pro-inflammatory mediators was seen in the brain of the infected Rag1-/- mice. Our findings thus showed that infection with influenza virus can lead to narcoleptic-like sleep-wake alterations in genetically susceptible subjects. Since the distribution in the brain of influenza virus after intranasal instillation seemed to reflect retrograde axonal transport from the olfactory bulb, the second experiment was focused on the verification of this monosynaptic connection. Unilateral injection of the fluorescent tracer Fluoro-Gold into the olfactory bulb in mice showed that neuronal cell bodies containing orexin/hypocretin, which are located in the lateral hypothalamus, were retrogradely labelled. The findings thus showed that these peptidergic neurons, which play a key role in wakefulness stability and sleep-wake transitions, project directly the olfactory bulb. The third experimental data set was focused on African trypanosomiasis. Staging of this disease is currently based on criteria that lack sensitivity. Since disease staging is needed for effective treatment of the patients, the study was aimed at the investigation of two potential biomarkers of the disease (sleep-wake alterations and levels of the chemokine CXCL10 in the cerebrospinal fluid) at the time of parasite invasion of the brain parenchyma. Sleep-wake changes characterize African trypanosomiasis in humans and in rodent models. The chemokine CXCL10 was previously found to play a key pathogenetic role in parasite neuroinvasion. Trypanosoma brucei brucei-infected rats were used as animal model. Interestingly, CXCL10 levels showed a steep increase in the serum at the time of parasite neuroinvasion and in the cerebrospinal fluid later during the disease. Neurophysiological long-term recordings indicated a progressive sleep-wake fragmentation and invasion of sleep by wakefulness at the time of parasite neuroinvasion.