Neuronal hyperexcitability is a DLK-dependent trigger of Herpes Simplex Virus reactivation that can be induced by IL-1
- University of Virginia, United States
- 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
Austin R Schinlever
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
- Melanie M Brinkmann, Technische Universität Braunschweig, Germany
Publication history
- 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)
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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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
Further reading
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- Cell Biology
- Microbiology and Infectious Disease
African trypanosomes proliferate as bloodstream forms (BSFs) and procyclic forms in the mammal and tsetse fly midgut, respectively. This allows them to colonise the host environment upon infection and ensure life cycle progression. Yet, understanding of the mechanisms that regulate and drive the cell replication cycle of these forms is limited. Using single-cell transcriptomics on unsynchronised cell populations, we have obtained high resolution cell cycle regulated (CCR) transcriptomes of both procyclic and slender BSF Trypanosoma brucei without prior cell sorting or synchronisation. Additionally, we describe an efficient freeze–thawing protocol that allows single-cell transcriptomic analysis of cryopreserved T. brucei. Computational reconstruction of the cell cycle using periodic pseudotime inference allowed the dynamic expression patterns of cycling genes to be profiled for both life cycle forms. Comparative analyses identify a core cycling transcriptome highly conserved between forms, as well as several genes where transcript levels dynamics are form specific. Comparing transcript expression patterns with protein abundance revealed that the majority of genes with periodic cycling transcript and protein levels exhibit a relative delay between peak transcript and protein expression. This work reveals novel detail of the CCR transcriptomes of both forms, which are available for further interrogation via an interactive webtool.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background:
Dog-mediated rabies is endemic across Africa causing thousands of human deaths annually. A One Health approach to rabies is advocated, comprising emergency post-exposure vaccination of bite victims and mass dog vaccination to break the transmission cycle. However, the impacts and cost-effectiveness of these components are difficult to disentangle.
Methods:
We combined contact tracing with whole-genome sequencing to track rabies transmission in the animal reservoir and spillover risk to humans from 2010-2020, investigating how the components of a One Health approach reduced the disease burden and eliminated rabies from Pemba Island, Tanzania. With the resulting high-resolution spatiotemporal and genomic data we inferred transmission chains and estimated case detection. Using a decision tree model we quantified the public health burden and evaluated the impact and cost-effectiveness of interventions over a ten-year time horizon.
Results:
We resolved five transmission chains co-circulating on Pemba from 2010 that were all eliminated by May 2014. During this period, rabid dogs, human rabies exposures and deaths all progressively declined following initiation and improved implementation of annual islandwide dog vaccination. We identified two introductions to Pemba in late 2016 that seeded re-emergence after dog vaccination had lapsed. The ensuing outbreak was eliminated in October 2018 through reinstated islandwide dog vaccination. While post-exposure vaccines were projected to be highly cost-effective ($256 per death averted), only dog vaccination interrupts transmission. A combined One Health approach of routine annual dog vaccination together with free post-exposure vaccines for bite victims, rapidly eliminates rabies, is highly cost-effective ($1657 per death averted) and by maintaining rabies freedom prevents over 30 families from suffering traumatic rabid dog bites annually on Pemba island.
Conclusions:
A One Health approach underpinned by dog vaccination is an efficient, cost-effective, equitable and feasible approach to rabies elimination, but needs scaling up across connected populations to sustain the benefits of elimination, as seen on Pemba, and for similar progress to be achieved elsewhere.
Funding:
Wellcome [207569/Z/17/Z, 095787/Z/11/Z, 103270/Z/13/Z], the UBS Optimus Foundation, the Department of Health and Human Services of the National Institutes of Health [R01AI141712] and the DELTAS Africa Initiative [Afrique One-ASPIRE/DEL-15-008] comprising a donor consortium of the African Academy of Sciences (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA), the New Partnership for Africa's Development Planning and Coordinating (NEPAD) Agency, Wellcome [107753/A/15/Z], Royal Society of Tropical Medicine and Hygiene Small Grant 2017 [GR000892] and the UK government. The rabies elimination demonstration project from 2010-2015 was supported by the Bill & Melinda Gates Foundation [OPP49679]. Whole-genome sequencing was partially supported from APHA by funding from the UK Department for Environment, Food and Rural Affairs (Defra), Scottish government and Welsh government under projects SEV3500 & SE0421.
