Neuronal hyperexcitability is a DLK-dependent trigger of Herpes Simplex Virus reactivation that can be induced by IL-1

  1. Sean R Cuddy
  2. Austin R Schinlever
  3. Sara Dochnal
  4. Philip V Seegren
  5. Jon Suzich
  6. Parijat Kundu
  7. Taylor K Downs
  8. Mina Farah
  9. Bimal N Desai
  10. Chris Boutell
  11. Anna R Cliffe  Is a corresponding author
  1. University of Virginia, United States
  2. MRC-University of Glasgow, United Kingdom

Abstract

Herpes Simplex Virus-1 (HSV-1) establishes a latent infection in neurons and periodically reactivates to cause disease. The stimuli that trigger HSV-1 reactivation have not been fully elucidated. We demonstrate HSV-1 reactivation from latently infected mouse neurons induced by forskolin requires neuronal excitation. Stimuli that directly induce neurons to become hyperexcitable also induced HSV-1 reactivation. Forskolin-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and included an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1β is released under conditions of stress, fever and UV exposure of the epidermis; all known triggers of clinical HSV reactivation. We found that IL-1β induced histone phosphorylation and increased the excitation in sympathetic neurons. Importantly, IL-1β triggered HSV-1 reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV-1 co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

Article and author information

Author details

  1. Sean R Cuddy

    Microbiology, Immunology and Cancer, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Austin R Schinlever

    Microbiology, Immunology and Cancer, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3401-0904
  3. Sara Dochnal

    Microbiology, Immunology and Cancer, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Philip V Seegren

    Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jon Suzich

    Microbiology, Immunology and Cancer, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6087-2893
  6. Parijat Kundu

    Microbiology, Immunology and Cancer, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1944-4579
  7. Taylor K Downs

    Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Mina Farah

    Microbiology, Immunology and Cancer, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Bimal N Desai

    Pharmacology, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3928-5854
  10. Chris Boutell

    Centre for Virus Research, MRC-University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Anna R Cliffe

    Microbiology, Immunology and Cancer, University of Virginia, Charlottesville, United States
    For correspondence
    cliffe@virginia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1136-5171

Funding

National Institute of Neurological Disorders and Stroke (R01NS105630)

  • Anna R Cliffe

National Institute of Allergy and Infectious Diseases (T32AI007046)

  • Sean R Cuddy
  • Jon Suzich

National Institute of General Medical Sciences (T32GM008136)

  • Sara Dochnal

National Institute of General Medical Sciences (T32GM007267)

  • Jon Suzich

National Eye Institute (F30EY030397)

  • Jon Suzich

Medical Research Council (MC_UU_12014/5)

  • Chris Boutell

National Institute of General Medical Sciences (GM108989)

  • Bimal N Desai

National Institute of General Medical Sciences (GM007055)

  • Philip V Seegren

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Rodent handling and husbandry were carried out under animal protocols approved by the Animal Care and Use Committee of the University of Virginia (UVA). All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#4134) of the University of Virginia.

Reviewing Editor

  1. Melanie M Brinkmann, Technische Universität Braunschweig, Germany

Publication history

  1. Received: April 17, 2020
  2. Accepted: December 14, 2020
  3. Accepted Manuscript published: December 22, 2020 (version 1)
  4. Accepted Manuscript updated: December 24, 2020 (version 2)
  5. Version of Record published: December 30, 2020 (version 3)

Copyright

© 2020, Cuddy et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sean R Cuddy
  2. Austin R Schinlever
  3. Sara Dochnal
  4. Philip V Seegren
  5. Jon Suzich
  6. Parijat Kundu
  7. Taylor K Downs
  8. Mina Farah
  9. Bimal N Desai
  10. Chris Boutell
  11. Anna R Cliffe
(2020)
Neuronal hyperexcitability is a DLK-dependent trigger of Herpes Simplex Virus reactivation that can be induced by IL-1
eLife 9:e58037.
https://doi.org/10.7554/eLife.58037
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