Neuronal hyperexcitability is a DLK-dependent trigger of Herpes Simplex Virus reactivation that can be induced by IL-1
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.
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
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.
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.
- Melanie M Brinkmann, Technische Universität Braunschweig, Germany
- Received: April 17, 2020
- Accepted: December 14, 2020
- Accepted Manuscript published: December 22, 2020 (version 1)
- Accepted Manuscript updated: December 24, 2020 (version 2)
- Version of Record published: December 30, 2020 (version 3)
© 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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