H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep–wake regulatory neurons in mice
- 14 December 2015
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 113 (3), 201521463-E377
- https://doi.org/10.1073/pnas.1521463112
Abstract
An increased incidence in the sleep-disorder narcolepsy has been associated with the 2009–2010 pandemic of H1N1 influenza virus in China and with mass vaccination campaigns against influenza during the pandemic in Finland and Sweden. Pathogenetic mechanisms of narcolepsy have so far mainly focused on autoimmunity. We here tested an alternative working hypothesis involving a direct role of influenza virus infection in the pathogenesis of narcolepsy in susceptible subjects. We show that infection with H1N1 influenza virus in mice that lack B and T cells (Recombinant activating gene 1-deficient mice) can lead to narcoleptic-like sleep–wake fragmentation and sleep structure alterations. Interestingly, the infection targeted brainstem and hypothalamic neurons, including orexin/hypocretin-producing neurons that regulate sleep–wake stability and are affected in narcolepsy. Because changes occurred in the absence of adaptive autoimmune responses, the findings show that brain infections with H1N1 virus have the potential to cause per se narcoleptic-like sleep disruption.Funding Information
- Vetenskapsrådet (VR K2012-99X-21765; 4X-2887)
- Karolinska Institutet (Not available)
This publication has 63 references indexed in Scilit:
- Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2Science Translational Medicine, 2015
- The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous systemThe Journal of Pathology, 2014
- Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System FunctionJournal of Neuroscience, 2014
- Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68The Journal of Immunology, 2012
- Human genetic susceptibility to infectious diseaseNature Reviews Genetics, 2012
- Common variants in P2RY11 are associated with narcolepsyNature Genetics, 2010
- A Case-Control Study of the Environmental Risk Factors for NarcolepsyNeuroepidemiology, 2007
- Influenza-associated acute encephalopathy in Japanese children in 1994–2002Virus Research, 2004
- Behavioral State Instability in Orexin Knock-Out MiceJournal of Neuroscience, 2004
- Genetic Ablation of Orexin Neurons in Mice Results in Narcolepsy, Hypophagia, and ObesityNeuron, 2001