RESUMEN
Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.
Asunto(s)
Encéfalo , Encefalitis por Herpes Simple , Herpesvirus Humano 1 , Proteínas de la Membrana , Internalización del Virus , Animales , Femenino , Humanos , Masculino , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/virología , Encefalitis por Herpes Simple/virología , Encefalitis por Herpes Simple/metabolismo , Herpesvirus Humano 1/patogenicidad , Herpesvirus Humano 1/fisiología , Homocigoto , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nectinas/genética , Nectinas/metabolismo , Neuronas/citología , Neuronas/metabolismo , Neuronas/virología , Células Madre Pluripotentes/citología , Replicación Viral , Preescolar , Adulto Joven , LinajeRESUMEN
Neste trabalho foram estudados 10 recem-nascidos com crises convulsivas idiopaticas a partir da segunda semana de vida. Houve um grupo com evoluçao favoravel e outro grupo de evoluçao ruim. Foi possivel distinguir estes grupos, clinica e eletrograficamente desde o inicio das crises. Os pacientes de boa evoluçao tinham crises clonicas alternantes e seguiam os criterios de evoluçao favoravel definidas em literatura. Aqueles de ma evoluçao apresentavam crises unilaterais, nao alternantes com outras caracteristicas de ma evoluçao ja constantes na literatura: constatou-se entao que, de acordo com os dados obtidos existem Convulsoes Neonatais Idiopaticas Benignas Tardias com piso na 3a. semana de vida. Suas caracteristicas sao proximas as descritas entre as convulsoes neonatais benignas idiopaticas (CNNIB) com pico em torno do quinto dia. Provavelmente estas tardias sao variantes das CNNIB