Encephalitis and poor neuronal death–mediated control of herpes simplex virus in human inherited RIPK3 deficiency

• DOI: 10.1126/sciimmunol.ade2860
• Publication Date: 2023-04-21T17:58:06Z
• Authors: Zhiyong Liu; Eduardo J. Garcia...; Oliver Harschnitz; Hongyan Guo; Yi-Hao Chan; Noopur V. Khobrekar; Mary L. Hasek; Kerry Dobbs; Darawan Rinchai; Marie Materna; Daniela Matuozzo; Danyel Lee; Paul Bastard; Jie Chen; Yoon Seung Lee; Seong K. Kim; Shuxiang Zhao; Param Amin; Lazaro Lorenzo; Yoann Seeleuthner; Remi Chevalier; Laure Mazzola; Claire Gay; Jean-Louis Stephan; Baptiste Milisavl...; Soraya Boucherit; Flore Rozenberg; Rebeca Perez de D...; Richard D. Dix; Nico Marr; Vivien Béziat; Aurelie Cobat; Mélodie Aubart; Laurent Abel; Stephane Chabrier; Gregory A. Smith; Luigi D. Notarangelo; Edward S. Mocarski; Lorenz Studer; Jean-Laurent Casa...; Shen-Ying Zhang
• Keywords: Cell Death; Receptors, Tumor Necrosis Factor, Type I; [SDV]Life Sciences [q-bio]; Receptor-Interacting Protein Serine-Threonine Kinases; 610; Humans; Herpes Simplex; Encephalitis, Herpes Simplex; Herpesvirus 1, Human; Article; 3. Good health; Toll-Like Receptor 3

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*) frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic regulating death outcomes, including apoptosis necroptosis. In vitro, the R422* P493fs9* proteins impaired cellular necroptosis upon TLR3, TLR4, or TNFR1 stimulation ZBP1/DAI-mediated necroptotic after HSV-1 infection. The patient’s fibroblasts displayed no detectable expression. After TLR3 stimulation, cells did not undergo infection, supported excessive despite normal induction antiviral IFN-β IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application exogenous IFN. human pluripotent stem (hPSC)–derived enhanced as isogenic RIPK3-knockout hPSC-derived neurons. Inherited deficiency therefore confers predisposition impairing death–dependent control but their production response IFNs.