Neuronal hyperexcitability is a DLK-dependent trigger of HSV-1 reactivation that can be induced by IL-1
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Abstract
Herpes Simplex Virus (HSV) establishes a latent infection in neurons and periodically reactivates to cause disease. The neuronal stimuli that trigger HSV reactivation have not been fully elucidated. Here we demonstrate that HSV reactivation can be induced by neuronal hyperexcitability. Neuronal stimulation-induced reactivation was dependent on voltage-gated ion and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, demonstrating that neuronal activity is required for reactivation. Hyperexcitability-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and progressed via an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1β induces neuronal hyperexcitability and is released under conditions of stress and fever; both known triggers of clinical HSV reactivation. IL-1β induced histone phosphorylation in sympathetic neurons, and importantly HSV reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation.
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###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on May 25, 2020, follows.
Summary
This work addresses the key question how the herpesvirus HSV-1 reactivates from latency in neurons and shows that neuronal excitability plays a major role for controlling latency and reactivation. How hyperexcitability might influence the behavior of a latent, neurotrophic virus was previously unknown, and the authors show that neuronal hyperexcitability induces HSV reactivation in a DLK/JNK-dependent manner. In additon, the authors identify the cytokine IL-1b as a stimulus that triggers HSV reactivation in neurons, dependent on neuronal excitability, which is also a novel finding and of great interest for the field.
Essential Revisions
The reviewers all agree that your work about the potential link …
###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on May 25, 2020, follows.
Summary
This work addresses the key question how the herpesvirus HSV-1 reactivates from latency in neurons and shows that neuronal excitability plays a major role for controlling latency and reactivation. How hyperexcitability might influence the behavior of a latent, neurotrophic virus was previously unknown, and the authors show that neuronal hyperexcitability induces HSV reactivation in a DLK/JNK-dependent manner. In additon, the authors identify the cytokine IL-1b as a stimulus that triggers HSV reactivation in neurons, dependent on neuronal excitability, which is also a novel finding and of great interest for the field.
Essential Revisions
The reviewers all agree that your work about the potential link between IL1b, neuronal hyperexcitability, and HSV-1 reactivation is very interesting. However, we think that the three experiments listed below would be needed to substantiate the conclusion regarding the link between these three elements.
To make sure that the results obtained with the inhibitors are not off-target effects, experiments with KO cells or siRNA knockdowns of DLK/JNK would strengthen the manuscript. Can you please specify in the manuscript the specific targets of the three inhibitors that were used - if they have discrete mechanisms of action, off-target effects may actually not be a problem. However, KO or knockdown experiments would validate the inhibitor results by an independent method and should be doable in these cultures.
To substantiate the very interesting finding with IL1b, an experiment with a neutralizing IL1b antibody should be performed to unequivocally show that IL1b induces reactivation (this would exclude that impurities in the cytokine batch such as LPS activate the cells).
To unequivocally show that IL1b induces reactivation through increasing neuronal hyperexcitability, calcium flux, which is induced by neuronal hyperexcitability, should be measured. A simple method to do this would be the use of Fura-2 AM or similar dyes. An advantage of this approach is that it could be measured what percentage of neurons are excited upon IL1b treatment and this could be correlated with the percentage of neurons that reactivate. This could also be performed in the presence of IL1b neutralizing antibodies to confirm that this cytokine induces neuronal hyperexcitability and HSV-1 reactivation.
These three additional experiments would make the report more robust and elegantly correlate hyperexcitability of neurons with HSV-1 reactivation.
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