RESUMO
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-ß 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.
Assuntos
Encefalite por Herpes Simples , Herpes Simples , Herpesvirus Humano 1 , Humanos , Morte Celular , Encefalite por Herpes Simples/genética , Herpesvirus Humano 1/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores Tipo I de Fatores de Necrose Tumoral , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismoRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the loss of lower and upper motor neurons leading to progressive muscle weakness and respiratory insufficiency. No treatment is currently available to cure ALS. Recent progress has led to the identification of several novel genetic determinants of this disease, including repeat expansions in the ataxin-2 (ATXN2) gene. Ataxin-2 is mislocalized in ALS patients and represents a relatively common susceptibility gene in ALS, making it a promising therapeutic target. In this review, we summarize genetic and pathological data implicating ataxin-2 in ALS, discuss potential disease mechanisms linked to altered ataxin-2 localization or function, and propose potential strategies for therapeutic intervention in ALS based on ataxin-2.