Neurons undergo IFNγ-driven persistent epigenetic shifts and synaptopathy in encephalitis, 2026, Shammas et al

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N_Dina

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Neurons undergo IFNγ-driven persistent epigenetic shifts and synaptopathy in encephalitis​

Shammas, Ghazal; Piccinno, Margot; Egervari, Kristof; Lemeille, Sylvain; Mariotte, Alexandre; Maltese, Federica; Panzeri, Alessandra; Wagner, Ingrid; Fonta, Nicolas; Furlan, Tiphaine; Kreutzfeldt, Mario; Vincenti, Ilena; Yermanos, Alexander; Page, Nicolas; Bellone, Camilla; Muñoz, Carmen Picon; Liberto, Giovanni Di; Merkler, Doron

In infectious and autoimmune disorders of the central nervous system, neurons can become cognate immunological targets of cytotoxic T cells, leading to persistent functional and synaptic impairments. However, the molecular underpinnings of such irreversible alterations remain unclear. Using a cytotoxic T cell-driven viral encephalitis mouse model, we found synaptic loss and altered neuronal excitability that outlasted the immune response in chronically diseased mice. Employing conditional reporter mice, bulk RNA sequencing (RNA-seq), single-nucleus RNA sequencing (snRNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and assay for transposase-accessible chromatin followed by sequencing (ATAC-seq), we mapped the trajectory of transient and sustained epigenetic shifts and transcriptional changes in neurons. Notably, virus-exposed neurons, as cognate targets of cytotoxic T cells, developed interferon-gamma (IFNγ)-mediated persistent chromatin closing, reducing transcription factor accessibility and downstream synaptic gene expression. Analogous synaptic transcriptional signatures were observed in neurons of human encephalitis. Our study identifies a novel IFNγ-driven neuronal epigenetic adaptation program underlying persistent synaptopathy with implications for chronic neuroinflammatory disorders.

Highlights​

• CD8+ T cell encephalitis triggers neuronal transcriptional and epigenetic shifts
• Persistent chromatin inaccessibility associates with reduced synaptic gene expression
• IFNγ drives non-cytolytic viral clearance, lasting epigenetic changes, and synaptopathy
• Rasmussen patient neurons share transcriptomic changes, supporting a conserved mechanism

Web (Cell) | DOI: 10.1016/j.neuron.2025.11.006
 
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Made a social media summary about this study:



1) Interesting study showing that a brain infection in mice can lead to loss of synapses and altered excitability of neurons that outlasts the immune response against the virus.

Changes are induced by interferon-gamma and involve epigenetic remodelling in the hippocampus.

2) In this experiment, neurons of mice were infected with a virus (non-cytolytic lymphocytic choriomeningitis virus, or LCMV). This created a cytotoxic T-cell response in the brain and a model to study viral encephalitis.

3) The mice got sick and had cognitive impairments but there was no significant neuronal loss. The virus was cleared without destroying cells. The authors did find altered neuronal connectivity and excitability. So the neurons weren't destroyed but they were working differently.

4) The researchers looked at what drove these changes and it seems to be the cytokine interferon-gamma. They found that it induced epigenetic changes that weren't seen in mice with deficient receptors for interferon-gamma (but it likely wasn't the only signal).

5) Interferon-gamma set a cascade in motion, a change in how genes are used or not. Chromatin and synapse-related genes were downregulated. This also happened in bystander neurons that weren't infected and was more strongly the case in the hippocampus than in the brainstem.

6) They found similar changes in hippocampal tissues of humans with a neuroinflammatory condition (Rasmussen encephalitis).

7) This study might be relevant to ME/CFS because in this illness there is a viral trigger of long-term, mostly neurological symptoms but without clear evidence of continued immune activation.

8 ) In addition, genes involved in synaptic plasticity such as Syngap1 that was studied in this mouse experiment have come up in genetic analyses of ME/CFS, such as the recent preprint by the Snyder group at Stanford.
https://www.medrxiv.org/con.../10.1101/2025.04.15.25325899v2
 
V.R.T. said:
I haven't heard of them being tried - i dont know much about them, could you explain their relevance to this paper?
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I know of HDACi and epigenetic changes as in the Post Finasteride Syndrome community (very different presentation than CFS) , where the leading theory is epigenetic changes to 5-alpha reductase expression, specifically over expression.

There was a big push to “reset” epigenetic changes by using a HADCi, specifically valporic acid. Highly frowned upon and for good reason, as the over expression theory has not been proven and valporic acid is a nasty drug. Their white paper and ongoing research should hopefully shed light on this in the future.

HADCi’s allow the chromatin to reopen allowing the reversal of epigenetic silencing. The thing is it affects so much more than this.
 
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Yeah, HDAC inhibitors are in the category of “only worth it if the patient has no other options and is already hurtling towards a painful death.” Some absurdly high percentage of cardiac events, plus the possibility of curing one cancer just to end up with another drug-induced cancer
 
Hutan said:
Here's the link to the Zhang et al study that @ME/CFS Science Blog mentions as highlighting the SYNGAP1 gene.
Dissecting the genetic complexity of Myalgic Encephalitis Chronic Fatigue syndrome via deep learning powered genome analysis, 2025, Zhang

That preprint got a lot of discussion on the forum. I'm surprised to see that it is still a preprint - I think?
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2 proteins directly involved in epigenetic modification were also highly ranked in that study: DNMT3A and HDAC1. #1 and 10, respectively (by p-value)
 
Screenshot 2026-03-12 at 11.12.35 AM.png

Notably, cytotoxic T cells can eliminate postmitotic neurons via lytic granzymes and perforins.6 While the resulting neuronal loss can correlate with neurological deficits,7 the severity of persistent dysfunction may not align with the extent of apparent tissue destruction detectable by clinical imaging.8 Rather than sheer neuronal cell death, persistent symptoms like recurrent seizures or cognitive decline may stem from structural and functional neuronal alterations affecting synaptic connectivity,9,10 ion channels,11 and neurotransmission.12 Such alterations compromise neuronal integration within neuronal networks, leading to various clinical manifestations.13
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Concurrently, non-cytolytic interactions between immune cells and neurons may serve as a protective mechanism against irreversible neuronal loss. In this context, pro-inflammatory cytokines, in particular interferon-gamma (IFNγ), play a central role in enabling the clearance of persistent viruses from neurons without inducing neuronal death.
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So, I'm thinking that if any expendable cell becomes infected with a virus, the cell is marked for killing, and it and the virus get promptly dealt with, broken down into parts. But, it's not going to end well if neurons get infected and the same approach is used - you don't want your neurons to be sacrificed. Instead, the CD8 T cells release interferon gamma which closes the chromatin in the neuron nucleus. That protects the DNA from damage - which makes sense if the cell is under attack from a virus (perhaps also if it is at risk from toxins too). Perhaps it ensures the cell's machinery can't be used by the virus to replicate?

Anyway, that's what they are showing in the middle picture there. The cell's nucleus is not open for business - genes are not being transcribed into proteins, including synaptic proteins. Fewer synapses means that the neuron isn't working as well. The third panel of the picture suggests a state where the closed chromatin state does not reverse, leaving the neuron with a low level of synapses.

So, I'm wondering, how could this apply to ME/CFS?

Could each episode of exertion somehow result in the T cells releasing interferon gamma, shutting down the chromatin and resulting in fewer functioning synapses? And then, slowly, things come right, the proteins get produced again and synaptic function resumes?

I think this could be true. Googling, it sounds as though the synapses rely on a constant supply of proteins to function. Active synapses require more proteins. Some of the proteins need to be replenished in a few hours; sounds as though a shut down of protein supply certainly could have a meaningful impact on function within a day or so.

I assume this could apply to neurons outside the brain too?

I'm excited, this seems to make sense with what we know. Do tell me if I have things wrong. Disclaimer: I've only read the first few paragraphs of this study.
 
Hutan said:
That protects the DNA from damage - which makes sense if the cell is under attack from a virus (perhaps also if it is at risk from toxins too). Perhaps it ensures the cell's machinery can't be used by the virus to replicate?
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The latter--the fatal damage to the cell is largely going to be happening outside the nucleus. Shutting down cellular machinery is a standard part of the interferon-mediated viral response, with the goal of making cells as hostile of an environment to viral replication as possible. Sort of like townsfolk torching fields and destroying infrastructure before fleeing an invading army.

Hutan said:
Could each episode of exertion somehow result in the T cells releasing interferon gamma, shutting down the chromatin and resulting in fewer functioning synapses? And then, slowly, things come right, the proteins get produced again and synaptic function resumes?
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The odds seem stacked against circulating T cells infiltrating the brain repeatedly in ME/CFS. This is a bit of a weird mouse model in that LCMV was injected directly into mouse brains, whereas most neurotrophic viruses in humans are dealt with at the meninges. The brain keeps its doors tightly shut for good reason--even if the neurons don't die, T cell infiltration can mediate encephalitis, seizures etc. When the brain does allow T cell infiltration, it's under a circumstance where it's the lesser evil.

That being said, sometimes people do experience T cell infiltration during an infection and are able to survive just fine. The main translational value of this study is showing that even if T cell infiltration was brief, the aftereffects from T-cell-derived IFN-g can be long-lasting because of the epigenetic imprintation in the neurons themselves. That might be relevant to something like persistent cognitive deficit after viral meningitis. Or maybe even to type I narcolepsy: one could hypothesize that the epigenetic repression in orexin and CRH neurons found in one study is an unfortunate permanent aftereffect of some circulating immune cells briefly making a pit spot at one part of the hypothalamus.
 
As for relevance to ME/CFS--
Per this study, sickness behavior in mice is mediated by type I (IFN-a or b, primarily) signaling in the brain, coming from brain endothelial cells rather than circulating immune cells:
Hutan

Thread 'Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment, 2016, Blank +'

Link

Thomas Blank 1 ∙ Claudia N. Detje 2 ∙ Alena Spieß 1 ∙ Nora Hagemeyer 1 ∙ Stefanie M. Brendecke 1 ∙ Jakob Wolfart 3 ∙ Ori Staszewski 1 ∙ Tanja Zöller 1 ∙ Ismini Papageorgiou 4 ∙ Justus Schneider 4 ∙ Ricardo Paricio-Montesinos 1 ∙ Ulrich L.M. Eisel 5∙ Denise Manahan-Vaughan 6 ∙ Stephan Jansen 6 ∙ Stefan Lienenklaus 2, 7 ∙ Bao Lu 8 ∙ Yumiko Imai 9 ∙ Marcus Müller 10 ∙ Susan E. Goelz 11 ∙ Darren P. Baker 12 ∙ Markus...
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It's possible that IFN-g from infiltrating T cells could cause similar symptoms. Either way, this study is evidence that many of the downstream changes induced by interferon exposure, which includes canonical interferon stimualted genes as well as all those synaptic genes, can be maintained long term epigenetically in neurons long after the infection itself and the T cells are gone (several of the differential genes in this study are induced by multiple types of interferon, which is why I'm not making the distinction).

So the potential relevance in ME/CFS is that something from initial infection gets locked in epigenetically in the brain. The next question would be whether that "locked in" thing is activation of the complicated neural pathways that mediate sickness behavior itself, or whether it's other epigenetic changes that predispose to an actual immune response to something that happens during exertion. The latter is basically my hypothesis for mtDNA and neuronal-derived type I interferon, so obviously I'm biased to speculate that way.
 
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