{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:46:16Z","timestamp":1792521976996,"version":"4.5.0"},"reference-count":74,"publisher":"Rockefeller University Press","issue":"1","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["786602"],"award-info":[{"award-number":["786602"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R359-2020-2287"],"award-info":[{"award-number":["R359-2020-2287"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R251-2017-1124"],"award-info":[{"award-number":["R251-2017-1124"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF23OC0084931"],"award-info":[{"award-number":["NNF23OC0084931"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF21OC0067157"],"award-info":[{"award-number":["NNF21OC0067157"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF20OC0064890"],"award-info":[{"award-number":["NNF20OC0064890"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020038","name":"Carlsberg Foundation","doi-asserted-by":"publisher","award":["CF17-0687"],"award-info":[{"award-number":["CF17-0687"]}],"id":[{"id":"10.13039\/100020038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001732","name":"Danish National Research Foundation","doi-asserted-by":"publisher","award":["DNRF164"],"award-info":[{"award-number":["DNRF164"]}],"id":[{"id":"10.13039\/501100001732","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2021-00942"],"award-info":[{"award-number":["2021-00942"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2024-02549"],"award-info":[{"award-number":["2024-02549"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011958","name":"Independent Research Fund Denmark","doi-asserted-by":"publisher","award":["0134-00006B"],"award-info":[{"award-number":["0134-00006B"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019180","name":"Horizon Europe European Research Council","doi-asserted-by":"publisher","award":["101057100"],"award-info":[{"award-number":["101057100"]}],"id":[{"id":"10.13039\/100019180","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005760","name":"Gothenburg University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005760","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1,5]]},"abstract":"<jats:p>Herpes simplex encephalitis (HSE) is a devastating disease with high mortality and serious sequelae. Genetic defects in the IFN-I pathway predispose individuals to HSE, but underlying mechanisms remain unclear. Using transgenic mice with the IRF3 R278Q mutation, ortholog to HSE-associated IRF3 R285Q, and iPSC-derived CNS cells from a pediatric patient carrying the variant, we investigated mechanisms in HSE. IRF3 R278Q transgenic mice exhibited aggravated HSV-1 brain disease and elevated CNS viral loads. Accordingly, microglia from the IRF3 R278Q mice showed reduced HSV-1\u2013induced IFN-I expression. Surprisingly, unaltered Ifnb levels along with elevated levels of inflammatory cytokines were detected in infected transgenic mouse brains, correlating with higher viral load. This was successfully modeled in patient microglia. Multiomics-based immune profiling revealed an inflammatory monocyte population in the infected IRF3 R278Q mouse brain, which was enriched for NF-\u03baB activation. NF-\u03baB inhibition improved disease outcomes, surpassing the effect of acyclovir. These findings suggest that IFN-I defects lead to elevated levels of HSV-1 replication in the brain, which subsequently enables NF-\u03baB\u2013driven immunopathology, offering insights with therapeutic potential.<\/jats:p>","DOI":"10.1084\/jem.20250064","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T06:20:46Z","timestamp":1755757246000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Role for NF-\u03baB in herpes encephalitis pathology in mice genocopying an inborn error of IRF3-IFN immunity"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6769-9165","authenticated-orcid":true,"given":"Manja","family":"Idorn","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2888-1219","authenticated-orcid":true,"given":"Xiangning","family":"Ding","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-7330","authenticated-orcid":true,"given":"Stefanie","family":"Fruhw\u00fcrth","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01tm6cn81","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg 3 Department of Psychiatry and Neurochemistry, , G\u00f6teborg,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3289-4139","authenticated-orcid":true,"given":"S\u00f8ren","family":"Holste","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8317-0886","authenticated-orcid":true,"given":"Line S.","family":"Reinert","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0639-6718","authenticated-orcid":true,"given":"Christian S.","family":"Skoven","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center of Functionally Integrative Neuroscience (CFIN), Aarhus University 4 Department Clinical Medicine, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2836-5448","authenticated-orcid":true,"given":"Katarina","family":"T\u00fcrner-Stenstr\u00f6m","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01tm6cn81","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg 3 Department of Psychiatry and Neurochemistry, , G\u00f6teborg,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6862-6679","authenticated-orcid":true,"given":"Alexander","family":"Schmitz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0431-2522","authenticated-orcid":true,"given":"Mikkel H.","family":"Vendelbo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/040r8fr65","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University Hospital 5 Department of Nuclear Medicine and PET, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3551-4173","authenticated-orcid":true,"given":"Benedicte P.","family":"Ulh\u00f8i","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/040r8fr65","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University Hospital 6 Department of Pathology, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9696-7982","authenticated-orcid":true,"given":"Dzeneta","family":"Vizlin-Hodzic","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01tm6cn81","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg 3 Department of Psychiatry and Neurochemistry, , G\u00f6teborg,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7832-4897","authenticated-orcid":true,"given":"Mona","family":"Wefelmeyer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2045-2509","authenticated-orcid":true,"given":"Ryo","family":"Narita","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4723-0438","authenticated-orcid":true,"given":"Lona J.","family":"Kroese","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xqtf034","id-type":"ROR","asserted-by":"publisher"}],"name":"Netherlands Cancer Institute 7 Animal Modeling Facility, , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2028-2573","authenticated-orcid":true,"given":"Ivo J.","family":"Huijbers","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xqtf034","id-type":"ROR","asserted-by":"publisher"}],"name":"Netherlands Cancer Institute 7 Animal Modeling Facility, , Amsterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3769-4902","authenticated-orcid":true,"given":"Michelle","family":"M\u00f8hlenberg","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5461-6893","authenticated-orcid":true,"given":"Anne Kruse","family":"Hollensen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0671-5581","authenticated-orcid":true,"given":"Xin","family":"Lai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7335-6436","authenticated-orcid":true,"given":"Marie B.","family":"Iversen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6391-9407","authenticated-orcid":true,"given":"Brian","family":"Hansen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center of Functionally Integrative Neuroscience (CFIN), Aarhus University 4 Department Clinical Medicine, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1853-9704","authenticated-orcid":true,"given":"Trine H.","family":"Mogensen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/040r8fr65","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University Hospital 8 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9180-4060","authenticated-orcid":true,"given":"S\u00f8ren R.","family":"Paludan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University 1 Department of Biomedicine, , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01aj84f44","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology of Viral infections, Aarhus University 2 , Aarhus,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/01tm6cn81","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Medicine, Sahlgrenska Academy, University of Gothenburg 9 Department of Rheumatology and Inflammation Research, , G\u00f6teborg,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"2025100909575027200_bib1","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.neuron.2005.03.018","article-title":"Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL","volume":"46","author":"Aktas","year":"2005","journal-title":"Neuron"},{"key":"2025100909575027200_bib2","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1084\/jem.20142274","article-title":"Functional IRF3 deficiency in a patient with herpes simplex encephalitis","volume":"212","author":"Andersen","year":"2015","journal-title":"J. Exp. Med."},{"key":"2025100909575027200_bib3","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.jaci.2011.04.059","article-title":"NEMO is a key component of NF-kappaB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus","volume":"128","author":"Audry","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025100909575027200_bib4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI139980","article-title":"Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency","volume":"131","author":"Bastard","year":"2021","journal-title":"J. Clin. Invest."},{"key":"2025100909575027200_bib5","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1210\/endo.138.1.4835","article-title":"Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro","volume":"138","author":"Behl","year":"1997","journal-title":"Endocrinology"},{"key":"2025100909575027200_bib6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI168321","article-title":"Human inherited complete STAT2 deficiency underlies inflammatory viral diseases","volume":"133","author":"Bucciol","year":"2023","journal-title":"J. Clin. Invest."},{"key":"2025100909575027200_bib7","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1074\/jbc.M209677200","article-title":"BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice","volume":"278","author":"Burke","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2025100909575027200_bib8","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1126\/science.1128346","article-title":"Herpes simplex virus encephalitis in human UNC-93B deficiency","volume":"314","author":"Casrouge","year":"2006","journal-title":"Science"},{"key":"2025100909575027200_bib9","doi-asserted-by":"publisher","first-page":"2807","DOI":"10.4049\/jimmunol.1203265","article-title":"Microglia and a functional type I IFN pathway are required to counter HSV-1-driven brain lateral ventricle enlargement and encephalitis","volume":"190","author":"Conrady","year":"2013","journal-title":"J. Immunol."},{"key":"2025100909575027200_bib10","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/s41586-024-07670-z","article-title":"TMEFF1 is a neuron-specific restriction factor for herpes simplex virus","volume":"632","author":"Dai","year":"2024","journal-title":"Nature"},{"key":"2025100909575027200_bib11","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022112907","article-title":"Viral recognition and the antiviral interferon response","volume":"42","author":"Dalskov","year":"2023","journal-title":"EMBO J."},{"key":"2025100909575027200_bib12","doi-asserted-by":"publisher","first-page":"11421","DOI":"10.1093\/nar\/gkaa873","article-title":"Characterization of distinct molecular interactions responsible for IRF3 and IRF7 phosphorylation and subsequent dimerization","volume":"48","author":"Dalskov","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2025100909575027200_bib75","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s12974-025-03471-x","article-title":"Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus CNS infection","volume":"22","author":"Ding","year":"2025","journal-title":"J. Neuroinflammation"},{"key":"2025100909575027200_bib14","doi-asserted-by":"publisher","first-page":"4378","DOI":"10.1093\/brain\/awad127","article-title":"Glucocorticoid-driven mitochondrial damage stimulates Tau pathology","volume":"146","author":"Du","year":"2023","journal-title":"Brain"},{"key":"2025100909575027200_bib15","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/ng1097","article-title":"Impaired response to interferon-alpha\/beta and lethal viral disease in human STAT1 deficiency","volume":"33","author":"Dupuis","year":"2003","journal-title":"Nat. Genet."},{"key":"2025100909575027200_bib16","doi-asserted-by":"publisher","first-page":"4564","DOI":"10.1128\/MCB.00146-10","article-title":"The type I interferon signaling pathway is a target for glucocorticoid inhibition","volume":"30","author":"Flammer","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"2025100909575027200_bib17","doi-asserted-by":"publisher","first-page":"1768","DOI":"10.4049\/jimmunol.164.4.1768","article-title":"Inhibition of Th1 immune response by glucocorticoids: Dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes","volume":"164","author":"Franchimont","year":"2000","journal-title":"J. Immunol."},{"key":"2025100909575027200_bib18","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf5808","article-title":"TREM2 is down-regulated by HSV1 in microglia and involved in antiviral defense in the brain","volume":"9","author":"Fruhw\u00fcrth","year":"2023","journal-title":"Sci. Adv."},{"key":"2025100909575027200_bib19","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s12974-019-1397-4","article-title":"CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis","volume":"16","author":"Funk","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"2025100909575027200_bib20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI134529","article-title":"TLR3 controls constitutive IFN-beta antiviral immunity in human fibroblasts and cortical neurons","volume":"131","author":"Gao","year":"2021","journal-title":"J. Clin. Invest."},{"key":"2025100909575027200_bib21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002250","article-title":"HSV infection induces production of ROS, which potentiate signaling from pattern recognition receptors: Role for S-glutathionylation of TRAF3 and 6","volume":"7","author":"Gonzalez Dosal","year":"2011","journal-title":"PLoS Pathog."},{"key":"2025100909575027200_bib22","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/1471-2105-10-106","article-title":"flowCore: a Bioconductor package for high throughput flow cytometry","volume":"10","author":"Hahne","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"2025100909575027200_bib23","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01783-21","article-title":"The astrocyte type I interferon response is essential for protection against herpes simplex encephalitis","volume":"96","author":"Hayes","year":"2022","journal-title":"J. Virol."},{"key":"2025100909575027200_bib24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009285","article-title":"ASC-dependent inflammasomes contribute to immunopathology and mortality in herpes simplex encephalitis","volume":"17","author":"Hayes","year":"2021","journal-title":"PLoS Pathog."},{"key":"2025100909575027200_bib25","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1084\/jem.20111316","article-title":"Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood","volume":"209","author":"Herman","year":"2012","journal-title":"J. Exp. Med."},{"key":"2025100909575027200_bib26","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1038\/nm1323","article-title":"IKK mediates ischemia-induced neuronal death","volume":"11","author":"Herrmann","year":"2005","journal-title":"Nat. Med."},{"key":"2025100909575027200_bib27","doi-asserted-by":"publisher","first-page":"3603","DOI":"10.1007\/s00415-023-11715-0","article-title":"Steroids for the treatment of viral encephalitis: A systematic literature review and meta-analysis","volume":"270","author":"Hodzic","year":"2023","journal-title":"J. Neurol."},{"key":"2025100909575027200_bib28","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.2383","article-title":"Vaginal HSV-2 infection and tissue analysis","volume":"7","author":"Iversen","year":"2017","journal-title":"Bio. Protoc."},{"key":"2025100909575027200_bib29","doi-asserted-by":"publisher","first-page":"5005","DOI":"10.1128\/JVI.00082-13","article-title":"Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes","volume":"87","author":"Johnson","year":"2013","journal-title":"J. Virol."},{"key":"2025100909575027200_bib30","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3389\/fnagi.2016.00175","article-title":"Pyrrolidine dithiocarbamate prevents neuroinflammation and cognitive dysfunction after endotoxemia in rats","volume":"8","author":"Kan","year":"2016","journal-title":"Front. Aging Neurosci."},{"key":"2025100909575027200_bib31","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01311-21","article-title":"Microglia activate early antiviral responses upon herpes simplex virus 1 entry into the brain to counteract development of encephalitis-like disease in mice","volume":"96","author":"Katzilieris-Petras","year":"2022","journal-title":"J. Virol."},{"key":"2025100909575027200_bib32","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1080\/13550280701460573","article-title":"Herpes simplex virus type 1 infection induces oxidative stress and the release of bioactive lipid peroxidation by-products in mouse P19N neural cell cultures","volume":"13","author":"Kavouras","year":"2007","journal-title":"J. Neurovirol."},{"key":"2025100909575027200_bib33","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1182\/blood-2003-08-2674","article-title":"Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9","volume":"103","author":"Krug","year":"2004","journal-title":"Blood"},{"key":"2025100909575027200_bib34","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1073\/pnas.0308057100","article-title":"Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis","volume":"101","author":"Kurt-Jones","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025100909575027200_bib35","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/nature11583","article-title":"Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells","volume":"491","author":"Lafaille","year":"2012","journal-title":"Nature"},{"key":"2025100909575027200_bib36","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.bcp.2017.07.011","article-title":"Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via expression of regulator of calcineurin activity 1 (RCAN1): Anti-inflammatory mechanism of PDTC through RCAN1 induction","volume":"143","author":"Lee","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"2025100909575027200_bib37","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/s41392-021-00687-0","article-title":"Pattern recognition receptors in health and diseases","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"2025100909575027200_bib38","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s12974-016-0515-9","article-title":"Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes","volume":"13","author":"Liddell","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"2025100909575027200_bib39","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.chom.2017.12.014","article-title":"Herpes simplex virus 1 VP22 inhibits AIM2-dependent inflammasome activation to enable efficient viral replication","volume":"23","author":"Maruzuru","year":"2018","journal-title":"Cell Host Microbe"},{"key":"2025100909575027200_bib40","doi-asserted-by":"publisher","DOI":"10.48550\/arXiv.1802.03426","article-title":"UMAP: Uniform Manifold approximation and projection for dimension reduction","author":"McInnes","year":"2020","journal-title":"arXiv"},{"key":"2025100909575027200_bib41","doi-asserted-by":"publisher","first-page":"11350","DOI":"10.1128\/JVI.01106-10","article-title":"Early innate recognition of herpes simplex virus in human primary macrophages is mediated via the MDA5\/MAVS-dependent and MDA5\/MAVS\/RNA polymerase III-independent pathways","volume":"84","author":"Melchjorsen","year":"2010","journal-title":"J. Virol."},{"key":"2025100909575027200_bib42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0145773","article-title":"Infiltration pattern of blood monocytes into the central nervous system during experimental herpes simplex virus encephalitis","volume":"10","author":"Menasria","year":"2015","journal-title":"PLoS One"},{"key":"2025100909575027200_bib43","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1159\/000492053","article-title":"A fatal case of herpes simplex encephalitis with two false-negative polymerase chain reactions","volume":"10","author":"Mendez","year":"2018","journal-title":"Case Rep. Neurol."},{"key":"2025100909575027200_bib44","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/BF00688578","article-title":"Herpes simplex encephalitis: An autopsy case with isolation of type 1 herpes simplex virus","volume":"40","author":"Miyake","year":"1977","journal-title":"Acta Neuropathol."},{"key":"2025100909575027200_bib45","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1128\/CMR.00046-08","article-title":"Pathogen recognition and inflammatory signaling in innate immune defenses","volume":"22","author":"Mogensen","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"2025100909575027200_bib46","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1161\/01.STR.0000120732.45951.26","article-title":"Nuclear factor-kappaB contributes to infarction after permanent focal ischemia","volume":"35","author":"Nurmi","year":"2004","journal-title":"Stroke"},{"key":"2025100909575027200_bib47","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1002\/jlb.67.1.18","article-title":"Synergistic action of pro-inflammatory agents: Cellular and molecular aspects","volume":"67","author":"Paludan","year":"2000","journal-title":"J. Leukoc. Biol."},{"key":"2025100909575027200_bib48","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.immuni.2010.08.014","article-title":"Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis","volume":"33","author":"P\u00e9rez de Diego","year":"2010","journal-title":"Immunity"},{"key":"2025100909575027200_bib49","doi-asserted-by":"publisher","first-page":"100902","DOI":"10.1016\/j.xpro.2021.100902","article-title":"Differentiation of functional astrocytes from human-induced pluripotent stem cells in chemically defined media","volume":"2","author":"Perriot","year":"2021","journal-title":"STAR Protoc."},{"key":"2025100909575027200_bib50","doi-asserted-by":"publisher","first-page":"13348","DOI":"10.1038\/ncomms13348","article-title":"Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defense in the CNS","volume":"7","author":"Reinert","year":"2016","journal-title":"Nat. Commun."},{"key":"2025100909575027200_bib51","doi-asserted-by":"publisher","DOI":"10.1172\/JCI136824","article-title":"Brain immune cells undergo cGAS\/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production","volume":"131","author":"Reinert","year":"2021","journal-title":"J. Clin. Invest."},{"key":"2025100909575027200_bib52","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022113118","article-title":"ER stress induces caspase-2-tBID-GSDME-dependent cell death in neurons lytically infected with herpes simplex virus type 2","volume":"42","author":"Ren","year":"2023","journal-title":"EMBO J."},{"key":"2025100909575027200_bib53","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.173066","article-title":"An IKBKE variant conferring functional cGAS\/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis","volume":"8","author":"Reyahi","year":"2023","journal-title":"JCI Insight"},{"key":"2025100909575027200_bib54","first-page":"2501","article-title":"Herpes simplex viruses","volume-title":"Fields Virology","author":"Roizman","year":"2007"},{"key":"2025100909575027200_bib55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005028","article-title":"Neuronal interferon signaling is required for protection against herpes simplex virus replication and pathogenesis","volume":"11","author":"Rosato","year":"2015","journal-title":"PLoS Pathog."},{"key":"2025100909575027200_bib56","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1038\/s41564-023-01405-y","article-title":"Modelling viral encephalitis caused by herpes simplex virus 1 infection in cerebral organoids","volume":"8","author":"Rybak-Wolf","year":"2023","journal-title":"Nat. Microbiol."},{"key":"2025100909575027200_bib57","doi-asserted-by":"publisher","first-page":"4889","DOI":"10.1172\/jci59259","article-title":"Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency","volume":"121","author":"Sancho-Shimizu","year":"2011","journal-title":"J. Clin. Invest."},{"key":"2025100909575027200_bib58","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1002\/glia.10274","article-title":"High-yield isolation of murine microglia by mild trypsinization","volume":"44","author":"Saura","year":"2003","journal-title":"Glia"},{"key":"2025100909575027200_bib59","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/s0140-6736(84)92623-0","article-title":"Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients","volume":"2","author":"Skoldenberg","year":"1984","journal-title":"Lancet"},{"key":"2025100909575027200_bib60","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1097\/QCO.0000000000000554","article-title":"Herpes simplex virus encephalitis update","volume":"32","author":"Stahl","year":"2019","journal-title":"Curr. Opin. Infect. Dis."},{"key":"2025100909575027200_bib61","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1007\/s11064-019-02779-4","article-title":"Mitochondrial dynamics impairment in dexamethasone-treated neuronal cells","volume":"44","author":"Suwanjang","year":"2019","journal-title":"Neurochem. Res."},{"key":"2025100909575027200_bib62","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/j.cell.2010.01.022","article-title":"Pattern recognition receptors and inflammation","volume":"140","author":"Takeuchi","year":"2010","journal-title":"Cell"},{"key":"2025100909575027200_bib63","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/cyto.a.22625","article-title":"FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data","volume":"87","author":"Van Gassen","year":"2015","journal-title":"Cytometry. A."},{"key":"2025100909575027200_bib64","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1002\/mrm.26059","article-title":"Diffusion MRI noise mapping using random matrix theory","volume":"76","author":"Veraart","year":"2016","journal-title":"Magn. Reson. Med."},{"key":"2025100909575027200_bib65","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.jot.2022.11.005","article-title":"Is dexamethasone-induced muscle atrophy an alternative model for naturally aged sarcopenia model?","volume":"39","author":"Wang","year":"2023","journal-title":"J. Orthop. Translat."},{"key":"2025100909575027200_bib66","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1172\/JCI97229","article-title":"Microglia are required for protection against lethal coronavirus encephalitis in mice","volume":"128","author":"Wheeler","year":"2018","journal-title":"J. Clin. Invest."},{"key":"2025100909575027200_bib67","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1212\/CON.0000000000000243","article-title":"Herpes simplex virus infections of the central nervous system","volume":"21","author":"Whitley","year":"2015","journal-title":"Continuum (Minneap Minn)"},{"key":"2025100909575027200_bib68","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","article-title":"ConsensusClusterPlus: A class discovery tool with confidence assessments and item tracking","volume":"26","author":"Wilkerson","year":"2010","journal-title":"Bioinformatics"},{"key":"2025100909575027200_bib69","doi-asserted-by":"publisher","first-page":"341","DOI":"10.3233\/JAD-2009-0963","article-title":"Alzheimer's disease-specific tau phosphorylation is induced by herpes simplex virus type 1","volume":"16","author":"Wozniak","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"2025100909575027200_bib70","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/2050-7771-2-1","article-title":"Monocyte and macrophage differentiation: Circulation inflammatory monocyte as biomarker for inflammatory diseases","volume":"2","author":"Yang","year":"2014","journal-title":"Biomark. Res."},{"key":"2025100909575027200_bib71","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s12974-024-03071-1","article-title":"Single-cell RNA sequencing reveals the immune features and viral tropism in the central nervous system of mice infected with Japanese encephalitis virus","volume":"21","author":"Yang","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"2025100909575027200_bib72","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41586-024-08119-z","article-title":"Genetic defects of brain immunity in childhood herpes simplex encephalitis","volume":"635","author":"Zhang","year":"2024","journal-title":"Nature"},{"key":"2025100909575027200_bib73","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1126\/science.1139522","article-title":"TLR3 deficiency in patients with herpes simplex encephalitis","volume":"317","author":"Zhang","year":"2007","journal-title":"Science"},{"key":"2025100909575027200_bib74","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.chom.2016.10.011","article-title":"A viral deamidase targets the helicase domain of RIG-I to block RNA-induced activation","volume":"20","author":"Zhao","year":"2016","journal-title":"Cell Host Microbe"}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20250064\/1951025\/jem_20250064.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20250064\/1951025\/jem_20250064.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T13:58:05Z","timestamp":1760018285000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/223\/1\/e20250064\/278357\/Role-for-NF-B-in-herpes-encephalitis-pathology-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,9]]},"references-count":74,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,5]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20250064","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,9]]},"article-number":"e20250064"}}