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Research Article

H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep–wake regulatory neurons in mice

Chiara Tesoriero, Alina Codita, Ming-Dong Zhang, Andrij Cherninsky, Håkan Karlsson, Gigliola Grassi-Zucconi, Giuseppe Bertini, Tibor Harkany, Karl Ljungberg, Peter Liljeström, Tomas G. M. Hökfelt, Marina Bentivoglio, and Krister Kristensson
  1. aDepartment of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
  2. bDepartment of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
  3. cSection of Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Huddinge 14157, Sweden;
  4. dDivision of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden;
  5. eDepartment of Brain Physiology, Institute of Biology of Taras Shevchenko National University, Kiev 01601, Ukraine;
  6. fDepartment of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna A-1090, Austria;
  7. gDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden

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PNAS January 19, 2016 113 (3) E368-E377; first published December 14, 2015; https://doi.org/10.1073/pnas.1521463112
Chiara Tesoriero
aDepartment of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
bDepartment of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
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Alina Codita
cSection of Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Huddinge 14157, Sweden;
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Ming-Dong Zhang
aDepartment of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
dDivision of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden;
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Andrij Cherninsky
eDepartment of Brain Physiology, Institute of Biology of Taras Shevchenko National University, Kiev 01601, Ukraine;
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Håkan Karlsson
aDepartment of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
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Gigliola Grassi-Zucconi
bDepartment of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
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Giuseppe Bertini
bDepartment of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
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Tibor Harkany
dDivision of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden;
fDepartment of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna A-1090, Austria;
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Karl Ljungberg
gDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden
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Peter Liljeström
gDepartment of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden
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Tomas G. M. Hökfelt
aDepartment of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
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  • For correspondence: tomas.hokfelt@ki.se krister.kristensson@ki.se
Marina Bentivoglio
bDepartment of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
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Krister Kristensson
aDepartment of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
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  • For correspondence: tomas.hokfelt@ki.se krister.kristensson@ki.se
  1. 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)

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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.

  • influenza A virus
  • lateral hypothalamus
  • orexin
  • locus coeruleus
  • noradrenaline

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.

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Influenza and narcolepsy in immune-deficient mice
Chiara Tesoriero, Alina Codita, Ming-Dong Zhang, Andrij Cherninsky, Håkan Karlsson, Gigliola Grassi-Zucconi, Giuseppe Bertini, Tibor Harkany, Karl Ljungberg, Peter Liljeström, Tomas G. M. Hökfelt, Marina Bentivoglio, Krister Kristensson
Proceedings of the National Academy of Sciences Jan 2016, 113 (3) E368-E377; DOI: 10.1073/pnas.1521463112

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Influenza and narcolepsy in immune-deficient mice
Chiara Tesoriero, Alina Codita, Ming-Dong Zhang, Andrij Cherninsky, Håkan Karlsson, Gigliola Grassi-Zucconi, Giuseppe Bertini, Tibor Harkany, Karl Ljungberg, Peter Liljeström, Tomas G. M. Hökfelt, Marina Bentivoglio, Krister Kristensson
Proceedings of the National Academy of Sciences Jan 2016, 113 (3) E368-E377; DOI: 10.1073/pnas.1521463112
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