TY - JOUR
T1 - Encephalitis and poor neuronal death-mediated control of herpes simplex virus in human inherited RIPK3 deficiency
AU - Liu, Zhiyong
AU - Reino, Eduardo J.Garcia
AU - Harschnitz, Oliver
AU - Guo, Hongyan
AU - Chan, Yi Hao
AU - Khobrekar, Noopur V.
AU - Hasek, Mary L.
AU - Dobbs, Kerry
AU - Rinchai, Darawan
AU - Materna, Marie
AU - Matuozzo, Daniela
AU - Lee, Danyel
AU - Bastard, Paul
AU - Chen, Jie
AU - Lee, Yoon Seung
AU - Kim, Seong K.
AU - Zhao, Shuxiang
AU - Amin, Param
AU - Lorenzo, Lazaro
AU - Seeleuthner, Yoann
AU - Chevalier, Remi
AU - Mazzola, Laure
AU - Gay, Claire
AU - Stephan, Jean Louis
AU - Milisavljevic, Baptiste
AU - Boucherit, Soraya
AU - Rozenberg, Flore
AU - de Diego, Rebeca Perez
AU - Dix, Richard D.
AU - Marr, Nico
AU - Béziat, Vivien
AU - Cobat, Aurelie
AU - Aubart, Mélodie
AU - Abel, Laurent
AU - Chabrier, Stephane
AU - Smith, Gregory A.
AU - Notarangelo, Luigi D.
AU - Mocarski, Edward S.
AU - Studer, Lorenz
AU - Casanova, Jean Laurent
AU - Zhang, Shen Ying
N1 - 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); the National Institutes of Health (NIH); the Clinical and Translational Science Award (CTSA) program, grant UL1TR001866; NIH grants R01AI088364, R01NS072381, R01AI020211, RO1 EY024630, R21 EY033215, P30CA008748R21AI151663 and NEI P30006360; 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; INSERM, Paris Cité University; and the St. Giles Foundation. L.D.N. is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. 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.
Publisher Copyright:
Copyright © 2023 The Authors.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
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U2 - 10.1126/sciimmunol.ade2860
DO - 10.1126/sciimmunol.ade2860
M3 - Article
C2 - 37083451
AN - SCOPUS:85153543944
SN - 2470-9468
VL - 8
JO - Science Immunology
JF - Science Immunology
IS - 82
M1 - eade2860
ER -
