{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:47:44Z","timestamp":1792669664022,"version":"4.5.0"},"reference-count":95,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"82","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Immunol."],"published-print":{"date-parts":[[2023,4,14]]},"abstract":"<jats:p>\n                    Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*)\n                    <jats:italic>RIPK3<\/jats:italic>\n                    variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1\/DAI-mediated necroptotic cell death after HSV-1 infection. The patient\u2019s fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient\u2019s cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-\u03b2 and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient\u2019s human pluripotent stem cell (hPSC)\u2013derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death\u2013dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.ade2860","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T13:58:06Z","timestamp":1682085486000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":49,"title":["Encephalitis and poor neuronal death\u2013mediated control of herpes simplex virus in human inherited RIPK3 deficiency"],"prefix":"10.1126","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6473-348X","authenticated-orcid":true,"given":"Zhiyong","family":"Liu","sequence":"first","affiliation":[{"name":"St.\u00a0Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New\u00a0York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4781-3864","authenticated-orcid":true,"given":"Eduardo J.","family":"Garcia Reino","sequence":"additional","affiliation":[{"name":"St.\u00a0Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New\u00a0York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6496-881X","authenticated-orcid":true,"given":"Oliver","family":"Harschnitz","sequence":"additional","affiliation":[{"name":"The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New\u00a0York, NY, USA."},{"name":"Human Technopole, Viale Rita Levi-Montalcini, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-1741","authenticated-orcid":true,"given":"Hongyan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory Vaccine Center, Emory University, GA, USA."},{"name":"School of Medicine, Atlanta, GA, USA."},{"name":"Louisiana State University Health Sciences Center at Shreveport (LSUHSC-S), Shreveport, LA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0329-238X","authenticated-orcid":true,"given":"Yi-Hao","family":"Chan","sequence":"additional","affiliation":[{"name":"St.\u00a0Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New\u00a0York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noopur V.","family":"Khobrekar","sequence":"additional","affiliation":[{"name":"The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New\u00a0York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8902-6431","authenticated-orcid":true,"given":"Mary L.","family":"Hasek","sequence":"additional","affiliation":[{"name":"St.\u00a0Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New\u00a0York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3432-3137","authenticated-orcid":true,"given":"Kerry","family":"Dobbs","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8851-7730","authenticated-orcid":true,"given":"Darawan","family":"Rinchai","sequence":"additional","affiliation":[{"name":"St.\u00a0Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New\u00a0York, NY, 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