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Contributed by Tomas G. M. Hökfelt, October 31, 2015 (sent for review July 16, 2015; reviewed by Antoine Adamantidis, Daniel Gonzalez-Dunia, Fang Han, and Thomas S. Kilduff)
Significance
Influenza A virus infections are risk factors for narcolepsy, a disease in which autoimmunity has been implicated. We tested experimentally whether influenza virus infections could be causally related to narcolepsy. We found that mice infected with a H1N1 influenza A virus strain developed over time sleep–wake changes described in murine models of narcolepsy and narcolepsy patients. In the brain, the virus infected orexin/hypocretin-producing neurons, which are destroyed in human narcolepsy, and other cells in the distributed sleep–wake-regulating neuronal network. The findings, obtained in mice lacking an adaptive autoimmune response, thus provide new avenues for research on infection-related mechanisms in narcolepsy.
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.
Footnotes
↵1C.T., A. Codita, and M.-D.Z. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: tomas.hokfelt{at}ki.se or krister.kristensson{at}ki.se.
Author contributions: T.G.M.H., M.B., and K.K. designed research; C.T., A. Codita, and M.-D.Z. performed research; K.L. and P.L. contributed new reagents/analytic tools; C.T., A. Codita, M.-D.Z., A. Cherninsky, H.K., G.G.-Z., G.B., T.H., T.G.M.H., M.B., and K.K. analyzed data; and H.K., T.G.M.H., M.B., and K.K. wrote the paper.
Reviewers: A.A., University of Bern; D.G.-D., INSERM; F.H., People’s Hospital Peking University; and T.S.K., SRI International.
The authors declare no conflict of interest.
See Commentary on page 476.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1521463112/-/DCSupplemental.
Influenza and narcolepsy in immune-deficient mice
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