Details

Autor(en) / Beteiligte

• Liu, Zhiyong
• Garcia Reino, Eduardo J
• Harschnitz, Oliver
• Guo, Hongyan
• Chan, Yi-Hao
• Khobrekar, Noopur V
• Hasek, Mary L
• Dobbs, Kerry
• Rinchai, Darawan
• Materna, Marie
• Matuozzo, Daniela
• Lee, Danyel
• Bastard, Paul
• Chen, Jie
• Lee, Yoon Seung
• Kim, Seong K
• Zhao, Shuxiang
• Amin, Param
• Lorenzo, Lazaro
• Seeleuthner, Yoann
• Chevalier, Remi
• Mazzola, Laure
• Gay, Claire
• Stephan, Jean-Louis
• Milisavljevic, Baptiste
• Boucherit, Soraya
• Rozenberg, Flore
• Perez de Diego, Rebeca
• Dix, Richard D
• Marr, Nico
• Béziat, Vivien
• Cobat, Aurelie
• Aubart, Mélodie
• Abel, Laurent
• Chabrier, Stephane
• Smith, Gregory A
• Notarangelo, Luigi D
• Mocarski, Edward S
• Studer, Lorenz
• Casanova, Jean-Laurent
• Zhang, Shen-Ying

Titel

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

Ist Teil von

• Science immunology, 2023-04, Vol.8 (82), p.eade2860

Ort / Verlag

United States

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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*) 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.