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


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/DAI-mediated 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-β 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.

SUBMITTER: Liu Z 

PROVIDER: S-EPMC10337828 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

Liu Zhiyong Z   Garcia Reino Eduardo J EJ   Harschnitz Oliver O   Guo Hongyan H   Chan Yi-Hao YH   Khobrekar Noopur V NV   Hasek Mary L ML   Dobbs Kerry K   Rinchai Darawan D   Materna Marie M   Matuozzo Daniela D   Lee Danyel D   Bastard Paul P   Chen Jie J   Lee Yoon Seung YS   Kim Seong K SK   Zhao Shuxiang S   Amin Param P   Lorenzo Lazaro L   Seeleuthner Yoann Y   Chevalier Remi R   Mazzola Laure L   Gay Claire C   Stephan Jean-Louis JL   Milisavljevic Baptiste B   Boucherit Soraya S   Rozenberg Flore F   Perez de Diego Rebeca R   Dix Richard D RD   Marr Nico N   Béziat Vivien V   Cobat Aurelie A   Aubart Mélodie M   Abel Laurent L   Chabrier Stephane S   Smith Gregory A GA   Notarangelo Luigi D LD   Mocarski Edward S ES   Studer Lorenz L   Casanova Jean-Laurent JL   Zhang Shen-Ying SY  

Science immunology 20230421 82


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*) <i>RIPK3</i> variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. I  ...[more]

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