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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Autor: García Reino, Eduardo Javier
Tipo de recurso: tesis doctoral
Fecha de publicación:2021
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/5457
Acceso en línea:https://hdl.handle.net/20.500.14352/5457
Access Level:acceso abierto
Palabra clave:616.831-002(043.2)
Herpes simplex virus encephalitis (HSE)
Encefalitis herpética (HSE)
Neurociencias (Medicina)
2490 Neurociencias
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oai_identifier_str oai:docta.ucm.es:20.500.14352/5457
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spelling Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitisMutaciones bialélicas en RIPK3 en un paciente con encefalitis herpéticaGarcía Reino, Eduardo Javier616.831-002(043.2)Herpes simplex virus encephalitis (HSE)Encefalitis herpética (HSE)Neurociencias (Medicina)2490 NeurocienciasLife-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.Universidad Complutense de MadridPerez de Diego, RebecaZhang, Shen-YingUniversidad Complutense de Madrid20212021-07-1220212021-07-12doctoral thesishttp://purl.org/coar/resource_type/c_db06info:eu-repo/semantics/doctoralThesisapplication/pdfhttps://hdl.handle.net/20.500.14352/5457reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/54572026-06-02T12:44:21Z
dc.title.none.fl_str_mv Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
Mutaciones bialélicas en RIPK3 en un paciente con encefalitis herpética
title Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
spellingShingle Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
García Reino, Eduardo Javier
616.831-002(043.2)
Herpes simplex virus encephalitis (HSE)
Encefalitis herpética (HSE)
Neurociencias (Medicina)
2490 Neurociencias
title_short Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
title_full Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
title_fullStr Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
title_full_unstemmed Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
title_sort Bi-allelic RIPK3 mutations in a patient with herpes simplex encephalitis
dc.creator.none.fl_str_mv García Reino, Eduardo Javier
author García Reino, Eduardo Javier
author_facet García Reino, Eduardo Javier
author_role author
dc.contributor.none.fl_str_mv Perez de Diego, Rebeca
Zhang, Shen-Ying
Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 616.831-002(043.2)
Herpes simplex virus encephalitis (HSE)
Encefalitis herpética (HSE)
Neurociencias (Medicina)
2490 Neurociencias
topic 616.831-002(043.2)
Herpes simplex virus encephalitis (HSE)
Encefalitis herpética (HSE)
Neurociencias (Medicina)
2490 Neurociencias
description 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.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-07-12
2021
2021-07-12
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/5457
url https://hdl.handle.net/20.500.14352/5457
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidad Complutense de Madrid
publisher.none.fl_str_mv Universidad Complutense de Madrid
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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