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1.
Proc Natl Acad Sci U S A ; 115(37): E8775-E8782, 2018 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-30154162

RESUMEN

Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Some HSE children carry inborn errors of the Toll-like receptor 3 (TLR3)-dependent IFN-α/ß- and -λ-inducing pathway. Induced pluripotent stem cell (iPSC)-derived cortical neurons with TLR3 pathway mutations are highly susceptible to HSV-1, due to impairment of cell-intrinsic TLR3-IFN immunity. In contrast, the contribution of cell-intrinsic immunity of human trigeminal ganglion (TG) neurons remains unclear. Here, we describe efficient in vitro derivation and purification of TG neurons from human iPSCs via a cranial placode intermediate. The resulting TG neurons are of sensory identity and exhibit robust responses to heat (capsaicin), cold (icilin), and inflammatory pain (ATP). Unlike control cortical neurons, both control and TLR3-deficient TG neurons were highly susceptible to HSV-1. However, pretreatment of control TG neurons with poly(I:C) induced the cells into an anti-HSV-1 state. Moreover, both control and TLR3-deficient TG neurons developed resistance to HSV-1 following pretreatment with IFN-ß but not IFN-λ. These data indicate that TG neurons are vulnerable to HSV-1 because they require preemptive stimulation of the TLR3 or IFN-α/ß receptors to induce antiviral immunity, whereas cortical neurons possess a TLR3-dependent constitutive resistance that is sufficient to block incoming HSV-1 in the absence of prior antiviral signals. The lack of constitutive resistance in TG neurons in vitro is consistent with their exploitation as a latent virus reservoir in vivo. Our results incriminate deficiencies in the constitutive TLR3-dependent response of cortical neurons in the pathogenesis of HSE.


Asunto(s)
Inmunidad/inmunología , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Receptor Toll-Like 3/metabolismo , Antivirales/farmacología , Diferenciación Celular/genética , Células Cultivadas , Corteza Cerebral/citología , Niño , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/fisiología , Humanos , Inmunidad/genética , Células Madre Pluripotentes Inducidas/citología , Interferón beta/farmacología , Mutación , Neuronas/efectos de los fármacos , Neuronas/virología , Poli I-C/farmacología , Receptor Toll-Like 3/genética , Ganglio del Trigémino/citología
2.
Cell Stem Cell ; 31(5): 734-753.e8, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38608707

RESUMEN

Autonomic parasympathetic neurons (parasymNs) control unconscious body responses, including "rest-and-digest." ParasymN innervation is important for organ development, and parasymN dysfunction is a hallmark of autonomic neuropathy. However, parasymN function and dysfunction in humans are vastly understudied due to the lack of a model system. Human pluripotent stem cell (hPSC)-derived neurons can fill this void as a versatile platform. Here, we developed a differentiation paradigm detailing the derivation of functional human parasymNs from Schwann cell progenitors. We employ these neurons (1) to assess human autonomic nervous system (ANS) development, (2) to model neuropathy in the genetic disorder familial dysautonomia (FD), (3) to show parasymN dysfunction during SARS-CoV-2 infection, (4) to model the autoimmune disease Sjögren's syndrome (SS), and (5) to show that parasymNs innervate white adipocytes (WATs) during development and promote WAT maturation. Our model system could become instrumental for future disease modeling and drug discovery studies, as well as for human developmental studies.


Asunto(s)
Diferenciación Celular , Disautonomía Familiar , Células Madre Pluripotentes , Humanos , Células Madre Pluripotentes/citología , Disautonomía Familiar/patología , Neuronas , Síndrome de Sjögren/patología , COVID-19/virología , COVID-19/patología , Animales , Sistema Nervioso Parasimpático , Células de Schwann , Ratones , SARS-CoV-2/fisiología
3.
Nat Med ; 25(12): 1873-1884, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31806906

RESUMEN

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-ß renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/ß stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.


Asunto(s)
Encefalitis por Herpes Simple/genética , Herpesvirus Humano 1/genética , Neuronas/inmunología , ARN Nucleolar Pequeño/genética , Adulto , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/virología , Preescolar , Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/patología , Encefalitis por Herpes Simple/virología , Femenino , Predisposición Genética a la Enfermedad , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/patogenicidad , Humanos , Inmunidad/genética , Lactante , Masculino , Metagenoma/genética , Metagenoma/inmunología , Persona de Mediana Edad , Neuronas/virología , ARN Nucleolar Pequeño/inmunología
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