{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:46:18Z","timestamp":1792521978112,"version":"4.5.0"},"reference-count":82,"publisher":"Rockefeller University Press","issue":"1","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/rupress.org\/pages\/terms102024"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1,5]]},"abstract":"<jats:p>Inborn errors of immunity (IEI) impairing brain-intrinsic immune defenses can underlie herpes simplex virus encephalitis. By whole-exome sequencing of cohorts of herpesvirus-associated recurrent lymphocytic meningitis and acute retinal necrosis, we identified two patients heterozygous for variants in interferon (IFN) regulatory factor 7 (IRF7). The expression of the Q185X (patient 1, P1) and A86Rfs23X (P2) IRF7 variants in HEK293T cells resulted in truncated IRF7 proteins that lacked IFN-transactivating ability. Peripheral blood mononuclear cells from P1 exhibited reduced type I IFN responses to HSV-2 infection. Genetic knock-in of the IRF7 Q185X variant in THP-1 cells and stem cell\u2013derived plasmacytoid dendritic cells (pDC) confirmed the disrupted IFN expression, resulting in impaired paracrine antiviral protection of meningeal fibroblasts. Strikingly, genetically heterozygous index patient pDC, but not those of healthy carrier family members, showed expression of only the pathogenic IRF7 Q185X allele, resulting in a homozygous transcriptotype. Collectively, this study identifies genetically heterozygous but transcriptionally homozygous IRF7 deficiency as an IEI underlying herpesvirus central nervous system infection.<\/jats:p>","DOI":"10.1084\/jem.20250492","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T06:20:55Z","timestamp":1758090055000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Genetically heterozygous - transcriptionally homozygous IRF7 deficiency underlies herpesvirus CNS infections in humans"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1200-807X","authenticated-orcid":true,"given":"Marvin","family":"Werner","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"]},{"id":[{"id":"https:\/\/ror.org\/040r8fr65","id-type":"ROR","asserted-by":"publisher"}],"name":"Aarhus University Hospital 3 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5690-7603","authenticated-orcid":true,"given":"Jonas Holst","family":"Wolff","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\/0009-0003-6343-8755","authenticated-orcid":true,"given":"Justin","family":"Taft","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj8s172","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Genetic Errors of Immunity, Columbia University 4 Department of Pediatrics, , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0866-4835","authenticated-orcid":true,"given":"Thomas","family":"Zillinger","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"]},{"name":"Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn 5 , Bonn,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3932-8762","authenticated-orcid":true,"given":"Dani\u00ebla M.","family":"Hinke","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 3 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3101-4777","authenticated-orcid":true,"given":"Toke S.","family":"Barfod","sequence":"additional","affiliation":[{"name":"Institute for Clinical Medicine, Copenhagen University 6 , Roskilde,","place":["Denmark"]},{"id":[{"id":"https:\/\/ror.org\/00363z010","id-type":"ROR","asserted-by":"publisher"}],"name":"Zealand University Hospital 7 Department of Infectious Diseases, , Roskilde,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8924-3997","authenticated-orcid":true,"given":"Kerstin","family":"De Keukeleere","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 3 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7186-7319","authenticated-orcid":true,"given":"Franziska","family":"Winzig","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 3 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6979-4256","authenticated-orcid":true,"given":"Bettina","family":"Bundgaard","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\/0009-0008-0959-880X","authenticated-orcid":true,"given":"Thomas Wisbech","family":"Skov","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\/0009-0002-9704-5442","authenticated-orcid":true,"given":"Julie A.","family":"Jensen","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 3 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2700-0882","authenticated-orcid":true,"given":"Sofie E.","family":"J\u00f8rgensen","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 3 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7156-1986","authenticated-orcid":true,"given":"Charlotte S.","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0417ye583","id-type":"ROR","asserted-by":"publisher"}],"name":"State Serum Institute 8 , Copenhagen,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9358-5500","authenticated-orcid":true,"given":"Morten K.","family":"Skouboe","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 3 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3910-7185","authenticated-orcid":true,"given":"Ria","family":"Lassauni\u00e8re","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0417ye583","id-type":"ROR","asserted-by":"publisher"}],"name":"State Serum Institute 8 , Copenhagen,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1712-3050","authenticated-orcid":true,"given":"Joke H.","family":"de Boer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0575yy874","id-type":"ROR","asserted-by":"publisher"}],"name":"University Medical Center, Utrecht 9 , Utrecht,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8847-9201","authenticated-orcid":true,"given":"Martin R.","family":"Jakobsen","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\/0000-0002-1322-3209","authenticated-orcid":true,"given":"Jacob G.","family":"Mikkelsen","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\/0000-0002-9277-3232","authenticated-orcid":true,"given":"Dusan","family":"Bogunovic","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj8s172","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Genetic Errors of Immunity, Columbia University 4 Department of Pediatrics, , New York, NY,","place":["USA"]}],"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"]},{"name":"Sahlgrenska Academy, University of Gothenburg 10 , Gothenburg,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7668-2517","authenticated-orcid":true,"given":"Ren\u00e9e M.","family":"van der Sluis","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\/0000-0002-1853-9704","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 3 Department of Infectious Diseases, , Aarhus,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"2025102909380457700_bib1","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/s41590-022-01415-8","article-title":"Mechanisms of myeloid cell entry to the healthy and diseased central nervous system","volume":"24","author":"Amann","year":"2023","journal-title":"Nat. Immunol."},{"key":"2025102909380457700_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":"2025102909380457700_bib3","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/nprot.2017.143","article-title":"CRISPR\/Cas9 genome editing in human hematopoietic stem cells","volume":"13","author":"Bak","year":"2018","journal-title":"Nat. Protoc."},{"key":"2025102909380457700_bib4","doi-asserted-by":"publisher","first-page":"e206","DOI":"10.1093\/infdis\/jiae321","article-title":"Severe West nile virus and severe acute respiratory syndrome coronavirus 2 infections in a patient with thymoma and anti\u2013type I interferon antibodies","volume":"231","author":"Barzaghi","year":"2024","journal-title":"J. Infect. Dis."},{"key":"2025102909380457700_bib5","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abl4340","article-title":"Autoantibodies neutralizing type I IFNs are present in \u223c4% of uninfected individuals over 70 years old and account for \u223c20% of COVID-19 deaths","volume":"6","author":"Bastard","year":"2021","journal-title":"Sci. Immunol."},{"key":"2025102909380457700_bib6","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. Investig."},{"key":"2025102909380457700_bib7","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd4585","article-title":"Autoantibodies against type I IFNs in patients with life-threatening COVID-19","volume":"370","author":"Bastard","year":"2020","journal-title":"Science"},{"key":"2025102909380457700_bib8","doi-asserted-by":"publisher","first-page":"3969","DOI":"10.1038\/s41467-024-48287-0","article-title":"Herpes simplex encephalitis due to a mutation in an E3 ubiquitin ligase","volume":"15","author":"Bibert","year":"2024","journal-title":"Nat. Commun."},{"key":"2025102909380457700_bib9","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1089\/crispr.2020.0022","article-title":"Deconvolution of complex DNA repair (DECODR): Establishing a novel deconvolution algorithm for comprehensive analysis of CRISPR-edited sanger sequencing data","volume":"4","author":"Bloh","year":"2021","journal-title":"CRISPR J."},{"key":"2025102909380457700_bib10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220202","article-title":"Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency","volume":"219","author":"Campbell","year":"2022","journal-title":"J. Exp. Med."},{"key":"2025102909380457700_bib11","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":"2025102909380457700_bib12","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1038\/s41586-024-07745-x","article-title":"Human TMEFF1 is a restriction factor for herpes simplex virus in the brain","volume":"632","author":"Chan","year":"2024","journal-title":"Nature"},{"key":"2025102909380457700_bib13","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A genomic mutational constraint map using variation in 76,156 human genomes","volume":"625","author":"Chen","year":"2024","journal-title":"Nature"},{"key":"2025102909380457700_bib14","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1126\/science.aaa1578","article-title":"Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency","volume":"348","author":"Ciancanelli","year":"2015","journal-title":"Science"},{"key":"2025102909380457700_bib15","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/s41587-019-0032-3","article-title":"CRISPResso2 provides accurate and rapid genome editing sequence analysis","volume":"37","author":"Clement","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"2025102909380457700_bib16","doi-asserted-by":"publisher","first-page":"958","DOI":"10.7326\/0003-4819-98-6-958","article-title":"Genital herpes simplex virus infections: Clinical manifestations, course, and complications","volume":"98","author":"Corey","year":"1983","journal-title":"Ann. Intern. Med."},{"key":"2025102909380457700_bib17","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":"2025102909380457700_bib18","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":"2025102909380457700_bib19","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":"2025102909380457700_bib20","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.3389\/fmicb.2019.01570","article-title":"Accurate quantification and characterization of adeno-associated viral vectors","volume":"10","author":"Dobnik","year":"2019","journal-title":"Front. Microbiol."},{"key":"2025102909380457700_bib21","doi-asserted-by":"publisher","first-page":"1952","DOI":"10.1128\/JVI.01578-08","article-title":"Role for plasmacytoid dendritic cells in the immune control of recurrent human herpes simplex virus infection","volume":"83","author":"Donaghy","year":"2009","journal-title":"J. Virol."},{"key":"2025102909380457700_bib22","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20212427","article-title":"Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic","volume":"219","author":"Duncan","year":"2022","journal-title":"J. Exp. Med."},{"key":"2025102909380457700_bib23","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":"2025102909380457700_bib24","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/s0022-1759(98)00170-7","article-title":"A statistically defined endpoint titer determination method for immunoassays","volume":"221","author":"Frey","year":"1998","journal-title":"J. Immunol. Methods"},{"key":"2025102909380457700_bib25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0272298","article-title":"Optimization and evaluation of a live virus SARS-CoV-2 neutralization assay","volume":"17","author":"Frische","year":"2022","journal-title":"PLoS One"},{"key":"2025102909380457700_bib26","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.jaci.2019.02.019","article-title":"Impaired control of multiple viral infections in a family with complete IRF9 deficiency","volume":"144","author":"Garc\u00eda-Morato","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025102909380457700_bib27","doi-asserted-by":"publisher","first-page":"3435","DOI":"10.1128\/MCB.01805-08","article-title":"Differential regulation of human interferon A gene expression by interferon regulatory factors 3 and 7","volume":"29","author":"G\u00e9nin","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"2025102909380457700_bib28","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20230661","article-title":"Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in \u223c40% of patients","volume":"220","author":"Gervais","year":"2023","journal-title":"J. Exp. Med."},{"key":"2025102909380457700_bib29","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/978-1-4939-0882-0_2","article-title":"Enzymatic synthesis and purification of a defined RIG-I ligand","volume":"1169","author":"Goldeck","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"2025102909380457700_bib30","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1084\/jem.20101568","article-title":"Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity","volume":"208","author":"Guo","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025102909380457700_bib31","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abc2691","article-title":"Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans","volume":"5","author":"Hait","year":"2020","journal-title":"Sci. Immunol."},{"key":"2025102909380457700_bib32","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1093\/infdis\/jiaa589","article-title":"Whole-exome sequencing of patients with recurrent HSV-2 lymphocytic Mollaret meningitis","volume":"223","author":"Hait","year":"2021","journal-title":"J. Infect. Dis."},{"key":"2025102909380457700_bib33","doi-asserted-by":"publisher","first-page":"1253040","DOI":"10.3389\/fnmol.2023.1253040","article-title":"Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-associated genetic variants","volume":"16","author":"Heinz","year":"2023","journal-title":"Front. Mol. Neurosci."},{"key":"2025102909380457700_bib34","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":"2025102909380457700_bib35","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/s0002-9394(14)70075-3","article-title":"Standard diagnostic criteria for the acute retinal necrosis syndrome","volume":"117","author":"Holland","year":"1994","journal-title":"Am. J. Ophthalmol."},{"key":"2025102909380457700_bib36","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1038\/nature03464","article-title":"IRF-7 is the master regulator of type-I interferon-dependent immune responses","volume":"434","author":"Honda","year":"2005","journal-title":"Nature"},{"key":"2025102909380457700_bib37","volume-title":"Fields Virology: DNA Viruses","author":"Howley","year":"2021"},{"key":"2025102909380457700_bib38","doi-asserted-by":"publisher","first-page":"13615","DOI":"10.1073\/pnas.1518646112","article-title":"The human gene damage index as a gene-level approach to prioritizing exome variants","volume":"112","author":"Itan","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025102909380457700_bib39","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.coi.2020.01.004","article-title":"Human inborn errors of immunity to herpes viruses","volume":"62","author":"Jouanguy","year":"2020","journal-title":"Curr. Opin. Immunol."},{"key":"2025102909380457700_bib40","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/nprot.2011.301","article-title":"AAV-mediated gene targeting methods for human cells","volume":"6","author":"Khan","year":"2011","journal-title":"Nat. Protoc."},{"key":"2025102909380457700_bib41","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"2025102909380457700_bib42","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1084\/jem.20050821","article-title":"Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection","volume":"202","author":"Kolumam","year":"2005","journal-title":"J. Exp. Med."},{"key":"2025102909380457700_bib43","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1038\/s41591-019-0672-3","article-title":"Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis","volume":"25","author":"Lafaille","year":"2019","journal-title":"Nat. Med."},{"key":"2025102909380457700_bib44","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65528","article-title":"Ascorbic acid supports ex vivo generation of plasmacytoid dendritic cells from circulating hematopoietic stem cells","volume":"10","author":"Laustsen","year":"2021","journal-title":"Elife"},{"key":"2025102909380457700_bib45","doi-asserted-by":"publisher","first-page":"723809","DOI":"10.3389\/fimmu.2021.723809","article-title":"Local immune control of latent herpes simplex virus type 1 in ganglia of mice and man","volume":"12","author":"Leger","year":"2021","journal-title":"Front. Immunol."},{"key":"2025102909380457700_bib46","doi-asserted-by":"publisher","first-page":"5602","DOI":"10.1128\/JVI.00143-15","article-title":"Viral infection of the central nervous system and neuroinflammation precede blood-brain barrier disruption during Japanese encephalitis virus infection","volume":"89","author":"Li","year":"2015","journal-title":"J. Virol."},{"key":"2025102909380457700_bib47","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adi0042","article-title":"Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis","volume":"9","author":"Li","year":"2024","journal-title":"Sci. Immunol."},{"key":"2025102909380457700_bib48","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1212\/WNL.0000000000000999","article-title":"TLR3 deficiency in herpes simplex encephalitis: High allelic heterogeneity and recurrence risk","volume":"83","author":"Lim","year":"2014","journal-title":"Neurology"},{"key":"2025102909380457700_bib49","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ade2860","article-title":"Encephalitis and poor neuronal death\u2013mediated control of herpes simplex virus in human inherited RIPK3 deficiency","volume":"8","author":"Liu","year":"2023","journal-title":"Sci. Immunol."},{"key":"2025102909380457700_bib50","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1136\/bmj.39409.673657.AE","article-title":"Viral meningitis","volume":"336","author":"Logan","year":"2008","journal-title":"BMJ"},{"key":"2025102909380457700_bib51","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1084\/jem.20030162","article-title":"Toll-like receptor 9\u2013mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells","volume":"198","author":"Lund","year":"2003","journal-title":"J. Exp. Med."},{"key":"2025102909380457700_bib52","doi-asserted-by":"publisher","first-page":"1236923","DOI":"10.3389\/fimmu.2023.1236923","article-title":"IRF7: Role and regulation in immunity and autoimmunity","volume":"14","author":"Ma","year":"2023","journal-title":"Front. Immunol."},{"key":"2025102909380457700_bib53","doi-asserted-by":"publisher","first-page":"6660","DOI":"10.1093\/emboj\/17.22.6660","article-title":"Differential viral induction of distinct interferon-\u03b1 genes by positive feedback through interferon regulatory factor-7","volume":"17","author":"Mari\u00e9","year":"1998","journal-title":"EMBO J."},{"key":"2025102909380457700_bib54","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abq4531","article-title":"GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141","volume":"7","author":"Naesens","year":"2022","journal-title":"Sci. Immunol."},{"key":"2025102909380457700_bib55","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1038\/s41423-024-01167-5","article-title":"The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond","volume":"21","author":"Ngo","year":"2024","journal-title":"Cell. Mol. Immunol."},{"key":"2025102909380457700_bib56","doi-asserted-by":"publisher","first-page":"2100568","DOI":"10.2807\/1560-7917.ES.2021.26.27.2100568","article-title":"SARS-CoV-2 neutralising antibody testing in Europe: Towards harmonisation of neutralising antibody titres for better use of convalescent plasma and comparability of trial data","volume":"26","author":"Nguyen","year":"2021","journal-title":"Euro Surveill."},{"key":"2025102909380457700_bib57","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/gene.2011.21","article-title":"IRF7: Activation, regulation, modification and function","volume":"12","author":"Ning","year":"2011","journal-title":"Genes Immun."},{"key":"2025102909380457700_bib58","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":"2025102909380457700_bib59","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT\u2013PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"2025102909380457700_bib60","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1093\/oxfordjournals.aje.a118408","article-title":"A simple method of estimating fifty per cent ENDPOINTS12","volume":"27","author":"Reed","year":"1938","journal-title":"Am. J. Epidemiol."},{"key":"2025102909380457700_bib61","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":"2025102909380457700_bib62","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. Investig."},{"key":"2025102909380457700_bib63","doi-asserted-by":"publisher","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: Predicting effects of amino acid substitutions on proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2025102909380457700_bib64","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20242179","article-title":"The common HAQ STING allele prevents clinical penetrance of COPA syndrome","volume":"222","author":"Simchoni","year":"2025","journal-title":"J. Exp. Med."},{"key":"2025102909380457700_bib65","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3390\/pathogens12020310","article-title":"Inborn errors of immunity predisposing to herpes simplex virus infections of the central nervous system","volume":"12","author":"Skouboe","year":"2023","journal-title":"Pathogens"},{"key":"2025102909380457700_bib66","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1038\/s41586-024-08346-4","article-title":"Monoallelic expression can govern penetrance of inborn errors of immunity","volume":"637","author":"Stewart","year":"2025","journal-title":"Nature"},{"key":"2025102909380457700_bib67","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1080\/23744235.2024.2365906","article-title":"Seroprevalence of human herpes viruses in France, 2018\u20132022: A multilevel regression and poststratification approach","volume":"56","author":"Supplisson","year":"2024","journal-title":"Infect. Dis."},{"key":"2025102909380457700_bib68","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003728","article-title":"Plasmacytoid dendritic cells contribute to systemic but not local antiviral responses to HSV infections","volume":"9","author":"Swiecki","year":"2013","journal-title":"PLoS Pathog."},{"key":"2025102909380457700_bib69","doi-asserted-by":"publisher","first-page":"2179","DOI":"10.1016\/S0002-9440(10)63575-4","article-title":"Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response","volume":"163","author":"Theil","year":"2003","journal-title":"Am. J. Pathol."},{"key":"2025102909380457700_bib70","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1007\/s00430-019-00623-8","article-title":"Defective interferon priming and impaired antiviral responses in a patient with an IRF7 variant and severe influenza","volume":"208","author":"Thomsen","year":"2019","journal-title":"Med. Microbiol. Immun."},{"key":"2025102909380457700_bib71","doi-asserted-by":"publisher","DOI":"10.1172\/JCI154016","article-title":"IRF7 and UNC93B1 variants in an infant with recurrent herpes simplex virus infection","volume":"133","author":"Tucker","year":"2023","journal-title":"J. Clin. Investig."},{"key":"2025102909380457700_bib72","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.jns.2018.11.018","article-title":"Mollaret meningitis","volume":"396","author":"Wright","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"2025102909380457700_bib73","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077846","article-title":"Single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides","volume":"8","author":"Yi","year":"2013","journal-title":"PLoS One"},{"key":"2025102909380457700_bib74","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1016\/j.celrep.2018.10.105","article-title":"Critical role of regulatory T cells in the latency and stress-induced reactivation of HSV-1","volume":"25","author":"Yu","year":"2018","journal-title":"Cell Rep."},{"key":"2025102909380457700_bib75","doi-asserted-by":"publisher","first-page":"4307","DOI":"10.1093\/bioinformatics\/bty536","article-title":"PopViz: A webserver for visualizing minor allele frequencies and damage prediction scores of human genetic variations","volume":"34","author":"Zhang","year":"2018","journal-title":"Bioinformatics"},{"key":"2025102909380457700_bib76","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd4570","article-title":"Inborn errors of type I IFN immunity in patients with life-threatening COVID-19","volume":"370","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"2025102909380457700_bib77","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220514","article-title":"Autoantibodies against type I IFNs in patients with critical influenza pneumonia","volume":"219","author":"Zhang","year":"2022","journal-title":"J. Exp. Med."},{"key":"2025102909380457700_bib78","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":"2025102909380457700_bib79","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/j.cell.2018.02.019","article-title":"Inborn errors of RNA lariat metabolism in humans with brainstem viral infection","volume":"172","author":"Zhang","year":"2018","journal-title":"Cell"},{"key":"2025102909380457700_bib80","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":"2025102909380457700_bib81","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01535-01519","article-title":"The IFNL4 gene is a noncanonical interferon gene with a unique but evolutionarily conserved regulation","volume":"94","author":"Zhou","year":"2019","journal-title":"J. Virol."},{"key":"2025102909380457700_bib82","doi-asserted-by":"publisher","first-page":"E8775","DOI":"10.1073\/pnas.1809853115","article-title":"Human iPSC-derived trigeminal neurons lack constitutive TLR3-dependent immunity that protects cortical neurons from HSV-1 infection","volume":"115","author":"Zimmer","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20250492\/1952445\/jem_20250492.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20250492\/1952445\/jem_20250492.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T13:38:14Z","timestamp":1761745094000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/223\/1\/e20250492\/278423\/Genetically-heterozygous-transcriptionally"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,29]]},"references-count":82,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,5]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20250492","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,29]]},"article-number":"e20250492"}}