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: | |
| 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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