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

Zhiyong Liu, Eduardo J.Garcia Reino, 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 SeeleuthnerRemi Chevalier, Laure Mazzola, Claire Gay, Jean Louis Stephan, Baptiste Milisavljevic, Soraya Boucherit, Flore Rozenberg, Rebeca Perez de Diego, 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 Casanova*, Shen Ying Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbereade2860
JournalScience Immunology
Issue number82
StatePublished - Apr 2023

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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