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

Article Article scientifique Article Neurons undergo IFNγ-driven persistent epigenetic shifts and synaptopathy in encephalitis eng 2025-12-24 2026-02-18 author Shammas Ghazal Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 931455 author Piccinno Margot Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 933426 author Egervari Kristof Levente 0000-0001-6763-9069 Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland. 761273 author Lemeille Sylvain Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 637517 Département de pathologie et immunologie (PATIM) author Mariotte Alexandre Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 930752 author Maltese Federica Department of Basic Neuroscience, University of Geneva, 1205 Geneva, Switzerland; Institute of Neuroscience, National Research Council, 20900 Vedano al Lambro, Italy. 981644 author Panzeri Alessandra Department of Basic Neuroscience, University of Geneva, 1205 Geneva, Switzerland. 983670 Département de neurosciences fondamentales (NEUFO) author Wagner Ingrid Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 604950 Département de pathologie et immunologie (PATIM) author Fonta Nicolas Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 779471 Département de pathologie et immunologie (PATIM) author Furlan Tiphaine Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 416764 Département de pathologie et immunologie (PATIM) author Kreutzfeldt Mario Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland. 736806 Département de pathologie et immunologie (PATIM) author Vincenti Ilena Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland. 692782 author Yermanos Alexander Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland; Center for Translational Immunology, University Medical Center Utrecht, 3584 EA Utrecht, the Netherlands. 943156 author Page Nicolas Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 796315 author Bellone Camilla 0000-0002-6774-6275 Department of Basic Neuroscience, University of Geneva, 1205 Geneva, Switzerland. 559161 Département de neurosciences fondamentales (NEUFO) author Picon Munoz Carmen Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland. 969332 Département de pathologie et immunologie (PATIM) author Di Liberto Giovanni Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Department of Clinical Neurosciences, Service of Neurology, Lausanne University Hospital and University of Lausanne, 1005 Lausanne, Switzerland. 848758 Département de neurosciences fondamentales (NEUFO) author Merkler Doron Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland. Electronic address: doron.merkler@unige.ch. 735735 Département de pathologie et immunologie (PATIM) 622-639.e11 10.1016/j.neuron.2025.11.006 41448185 0896-6273 https://www.sciencedirect.com/science/article/pii/S0896627325008530 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. Chromatin remodeling Cytotoxic T cell Encephalitis Multi-omics Neuron Non-cytolytic viral clearance Synaptic loss Transcriptional adaptation Animals Mice Interferon-gamma / metabolism Epigenesis, Genetic Neurons / metabolism Neurons / pathology Neurons / immunology Synapses / pathology Synapses / metabolism Humans Encephalitis / pathology Encephalitis / genetics Encephalitis / immunology Encephalitis / metabolism Mice, Transgenic Disease Models, Animal T-Lymphocytes, Cytotoxic / immunology Mice, Inbred C57BL Dewey 616.8 Dewey 616.07 Swiss National Science Foundation Regulators of long-term dyshomeostasis in chronic neuroinflammation 215050 CH Swiss National Science Foundation Deciphering transcriptional regulators of T cell fate decisions in CNS autoimmunity 201271 CH European Commission Molecular pathology of anti-viral T cell responses in the central nervous system 865026 PATHOCODE EU H2020 137 Département de pathologie et immunologie 21F 53 Département de neurosciences fondamentales 21A false 565 La Sclérose en plaques 908 973 Les dysfonctions synaptiques du cerveau 971 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE288606 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE289107 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE289108 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE110593 Neuron 114 4 04d99a82-03c0-43a4-9a67-5f424edc2861 Article (Published version) Public file.pdf 15978596 application/pdf CC BY-4.0 86d29ae045ecb61e65b171e67687a329e35413060de328a4285f9f2baa1b37b3 fe1e6b50-36b1-4d4f-bb2f-7ea416487c57 Supplemental data Public 1-s2.0-S0896627325008530-mmc1.pdf 3555763 application/pdf CC BY-4.0 641c17494376bc1c5b23f86dd268107f655ed2f7aedbaf5071936b4edc5653f5 Vignette Public 1-s2.0-S0896627325008530-fx1_lrg.jpg 294942 image/png openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine fondamentale / Département de neurosciences fondamentales

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Neurons undergo IFNγ-driven persistent epigenetic shifts and synaptopathy in encephalitis	Neuron			2026	11	23

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