Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
Life-threatening herpes simplex virus encephalitis (HSE) is the most common form of sporadic viral encephalitis worldwide. A diverse collection of genetic etiologies can predispose to this condition: inborn errors of the TLR3 responsive pathway impair central nervous system (CNS) cortical neuron- an...
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| Tipo de documento: | tese |
| Data de publicação: | 2021 |
| País: | España |
| Recursos: | Universidad Complutense de Madrid (UCM) |
| Repositório: | Docta Complutense |
| Idioma: | inglês |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/5457 |
| Acesso em linha: | https://hdl.handle.net/20.500.14352/5457 |
| Access Level: | Acceso aberto |
| Palavra-chave: | 616.831-002(043.2) Herpes simplex virus encephalitis (HSE) Encefalitis herpética (HSE) Neurociencias (Medicina) 2490 Neurociencias |
| Resumo: | Life-threatening herpes simplex virus encephalitis (HSE) is the most common form of sporadic viral encephalitis worldwide. A diverse collection of genetic etiologies can predispose to this condition: inborn errors of the TLR3 responsive pathway impair central nervous system (CNS) cortical neuron- and oligodendrocyte-intrinsic immunity to herpes simplex virus type 1 (HSV-1) and underlie forebrain HSE; heterozygous SNORA31 variants have also been associated with forebrain HSE; last, genetic defects of RNA lariat metabolism, due to mutations in DBR1, can trigger brainstem HSE. Still, the vast majority of HSE patients enrolled in our cohort lack a genetic diagnose. Here, we report autosomal recessive RIPK3 deficiency in a patient with recurrent forebrain HSE. The patient is compound heterozygous for one nonsense and one frameshift RIPK3 mutations that lead to impaired protein expression and function of RIPK3 via distinct mechanisms. We show that the patient’s fibroblasts do not phosphorylate MLKL upon stimulation via TNFR1 or TLR3, while the production of IFN-b or -l was normal upon TLR3 activation. We further demonstrate that the TLR3-induced RIPK3-dependent necroptosis signaling cascade is selectively impaired in fibroblasts from previously described patients with TLR3 pathway deficiencies. Taken together, our findings suggest that RIPK3 deficiency predisposes to HSE, due to disruption of the TLR3-RIPK3-mediated necroptosis pathway. This novel genetic etiology expands our understanding of the TLR3 circuit as a non-redundant mechanism of antiviral immunity of the CNS in humans. |
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