Narcolepsy is a rare neurological sleep disorder. However, after the beginning of the influenza A (H1N1) pandemic, an increased incidence of narcolepsy was observed, especially in young people aged between 4-19 years. In the present study, infection of Rag1-/- (lacking B and T cells) and wild-type mice with a mouse-neuroadapted or a 2009 H1N1 influenza A virus strain was used to elucidate pathogenetic mechanisms. Electroencephalogram (EEG) and actimetry were recorded by NeuroLogger® device which allows the mouse to move freely in its cage. Infected mice were sacrificed following the onset of sickness signs and brain samples were collected. In Rag1-/- mice, immunohistochemistry for antigens of the mouse-neuroadapted influenza strain showed hypothalamic and upper brainstem viral localization, including neurons involved in sleep-wakefulness regulation. Moreover, preliminary EEG analyses showed severe changes in the sleep-wake pattern in the infected Rag1-/- mice. Levels of viral RNA and inflammatory markers were analysed by RT-PCR. Interestingly, preliminary data indicate that the presence of transcripts encoding the non-structural viral protein (NS1) in the brain of mice infected with either viral strain was transient in wild-type mice, but persisted in the Rag1-/- mice. Up-regulation of transcripts of inducible nitric oxide synthase was seen in infected wild-type mice. In conclusion, our data suggest that infection of wild-type and Rag1-/- mice may provide useful models to study changes in sleep patterns caused by H1N1 influenza A virus strains, and may increase our understanding of the role of direct viral versus innate and adaptive immune response effects. (Supported by Swedish MPA)
Sleep and influenza A viral infections in murine models
TESORIERO, Chiara;COLAVITO, Valeria;BENTIVOGLIO FALES, Marina;
2014-01-01
Abstract
Narcolepsy is a rare neurological sleep disorder. However, after the beginning of the influenza A (H1N1) pandemic, an increased incidence of narcolepsy was observed, especially in young people aged between 4-19 years. In the present study, infection of Rag1-/- (lacking B and T cells) and wild-type mice with a mouse-neuroadapted or a 2009 H1N1 influenza A virus strain was used to elucidate pathogenetic mechanisms. Electroencephalogram (EEG) and actimetry were recorded by NeuroLogger® device which allows the mouse to move freely in its cage. Infected mice were sacrificed following the onset of sickness signs and brain samples were collected. In Rag1-/- mice, immunohistochemistry for antigens of the mouse-neuroadapted influenza strain showed hypothalamic and upper brainstem viral localization, including neurons involved in sleep-wakefulness regulation. Moreover, preliminary EEG analyses showed severe changes in the sleep-wake pattern in the infected Rag1-/- mice. Levels of viral RNA and inflammatory markers were analysed by RT-PCR. Interestingly, preliminary data indicate that the presence of transcripts encoding the non-structural viral protein (NS1) in the brain of mice infected with either viral strain was transient in wild-type mice, but persisted in the Rag1-/- mice. Up-regulation of transcripts of inducible nitric oxide synthase was seen in infected wild-type mice. In conclusion, our data suggest that infection of wild-type and Rag1-/- mice may provide useful models to study changes in sleep patterns caused by H1N1 influenza A virus strains, and may increase our understanding of the role of direct viral versus innate and adaptive immune response effects. (Supported by Swedish MPA)
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