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

• Type of Material: Article
• Authors: Zhiyong Liu, Rockefeller University; Eduardo J. Garcia Reino, Rockefeller University; Oliver Harschnitz, Sloan Kettering Institute for Cancer Research, New York; Hongyan Guo, Emory University; Yi-Hao Chan, Rockefeller University; Noopur Khobrekar, Sloan Kettering Institute for Cancer Research, New York; Mary L Hasek, Rockefeller University; Kerry Dobbs, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Darawan Rinchai, Rockefeller University; Marie Materna, Paris City University; Daniela Matuozzo, Paris City University; Danyel Lee, Rockefeller University; Paul Bastard, Rockefeller University; Jie Chen, Rockefeller University; Yoon Seung Lee, Rockefeller University; Seong K Kim, Louisiana State University; Shuxiang Zhao, Rockefeller University; Param Amin, Sloan Kettering Institute for Cancer Research, New York; Lazaro Lorenzo, Necker Hospital for Sick Children, Paris; Yoann Seeleuthner, Necker Hospital for Sick Children, Paris; Remi Chevalier, Necker Hospital for Sick Children, Paris; Laure Mazzola, Hôpital Nord, Saint-Etienne; Claire Gay, Hôpital Nord, Saint-Etienne; Jean-Louis Stephan, Hôpital Nord, Saint-Etienne; Baptiste Milisavljevic, Rockefeller University; Soraya Boucherit, Necker Hospital for Sick Children, Paris; Flore Rozenberg, Cochin Hospital, Paris; Rebeca Perez de Diego, IdiPAZ Institute for Health Research; Richard D Dix, Emory University; Nico Marr, Sidra Medicine, Doha; Vivien Béziat, Rockefeller University; Aurelie Cobat, Rockefeller University; Mélodie Aubart, Necker Hospital for Sick Children, Paris; Laurent Abel, Rockefeller University; Stephane Chabrier, Hôpital Nord, Saint-Etienne; Gregory A Smith, Northwestern University Feinberg; Luigi D Notarangelo, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Edward S Mocarski, Emory University; Lorenz Studer, Sloan Kettering Institute for Cancer Research, New York; Jean-Laurent Casanova, Rockefeller University; Shen-Ying Zhang, Rockefeller University
• Language: English
• Date: 2023-04-01
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2024 American Association for the Advancement of Science. All rights reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciimmunol.ade2860
• Title of Journal or Parent Work: Science Immunology
• Volume: 8
• Issue: 82
• Start Page: eade2860
• End Page: eade2860
• Grant/Funding Information: This work was conducted in the two branches of the Laboratory of Human Genetics of Infectious Diseases, and was funded in part by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Clinical and Translational Science Award (CTSA) program, grant UL1TR001866, NIH grants R01AI088364, R01NS072381, R01AI020211 and R21AI151663, grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the “Investments for the future” program (ANR-10-IAHU-01), the ANR grants IEIHSEER (ANR-14-CE14-0008-01), SEAeHostFactors (ANR-18-CE15-0020-02), and CNSVIRGEN (ANR-19-CE15-0009-01), the French Foundation for Medical Research (FRM) (EQU201903007798), the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cité University, and the St. Giles Foundation. LDN is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Y.H.C. was supported by the A*STAR International Fellowship (AIF). P.B. was supported by the FRM (EA20170638020) and the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt Schueller). E.S.M. is supported by NIH grant R01AI020211.
• Keywords: Toll-Like Receptor 3; Receptor-Interacting Protein Serine-Threonine Kinases; Herpes Simplex; Cell Death; Encephalitis, Herpes Simplex; Humans; Receptors, Tumor Necrosis Factor, Type I; Herpesvirus 1, Human
• Research Categories: Biology, Virology; Biology, Neuroscience; Biology, Cell; Health Sciences, Immunology; Biology, Microbiology; Biology, Genetics

Abstract

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∗) RIPK3 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/DAImediated necroptotic cell death after HSV-1 infection. The patient's fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient's cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-â and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient's human pluripotent stem cell (hPSC)-derived 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-dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.