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

   


Authors: Liu, Z.; Garcia Reino, E. J.; Harschnitz, O.; Guo, H.; Chan, Y. H.; Khobrekar, N. V.; Hasek, M. L.; Dobbs, K.; Rinchai, D.; Materna, M.; Matuozzo, D.; Lee, D.; Bastard, P.; Chen, J.; Lee, Y. S.; Kim, S. K.; Zhao, S.; Amin, P.; Lorenzo, L.; Seeleuthner, Y.; Chevalier, R.; Mazzola, L.; Gay, C.; Stephan, J. L.; Milisavljevic, B.; Boucherit, S.; Rozenberg, F.; Perez de Diego, R.; Dix, R. D.; Marr, N.; Béziat, V.; Cobat, A.; Aubart, M.; Abel, L.; Chabrier, S.; Smith, G. A.; Notarangelo, L. D.; Mocarski, E. S.; Studer, L.; Casanova, J. L.; Zhang, S. Y.
Article Title: 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.
Journal Title: Science Immunology
Volume: 8
Issue: 82
ISSN: 2470-9468
Publisher: Amer Assoc Advancement Science  
Date Published: 2023-04-01
Start Page: eade2860
Language: English
DOI: 10.1126/sciimmunol.ade2860
PUBMED: 37083451
PROVIDER: scopus
PMCID: PMC10337828
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85153543944&doi=10.1126%2fsciimmunol.ade2860&partnerID=40&md5=08db78b7e74222fd2764ba362cd13330
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Export Date: 1 May 2023 -- Source: Scopus
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MSK Authors
  1. Lorenz Studer
    224 Studer
  2. Oliver Harschnitz
    11 Harschnitz
  3. Noopur V. Khobrekar
    4 Khobrekar
  4. Param Amin
    2 Amin
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