RESUMEN
The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively4-6. Notably, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.
Asunto(s)
Factores de Restricción Antivirales , Encéfalo , Herpes Simple , Herpesvirus Humano 1 , Proteínas de la Membrana , Neuronas , Internalización del Virus , Replicación Viral , Animales , Femenino , Humanos , Masculino , Ratones , Factores de Restricción Antivirales/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/virología , Muerte Celular , Sistemas CRISPR-Cas/genética , Herpes Simple/inmunología , Herpes Simple/metabolismo , Herpes Simple/virología , Herpesvirus Humano 1/crecimiento & desarrollo , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/fisiología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Neuronas/virología , Neuronas/metabolismo , Carga Viral , Nectinas/metabolismo , Miosina Tipo IIA no Muscular/metabolismo , Miosina Tipo IIB no Muscular/metabolismo , Interferón Tipo I , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/prevención & control , Enfermedades Neuroinflamatorias/virologíaRESUMEN
Pattern recognition receptors (PRRs) induce host defense but can also induce exacerbated inflammatory responses. This raises the question of whether other mechanisms are also involved in early host defense. Using transcriptome analysis of disrupted transcripts in herpes simplex virus (HSV)-infected cells, we find that HSV infection disrupts the hypoxia-inducible factor (HIF) transcription network in neurons and epithelial cells. Importantly, HIF activation leads to control of HSV replication. Mechanistically, HIF activation induces autophagy, which is essential for antiviral activity. HSV-2 infection in vivo leads to hypoxia in CNS neurons, and mice with neuron-specific HIF1/2α deficiency exhibit elevated viral load and augmented PRR signaling and inflammatory gene expression in the CNS after HSV-2 infection. Data from human stem cell-derived neuron and microglia cultures show that HIF also exerts antiviral and inflammation-restricting activity in human CNS cells. Collectively, the HIF transcription factor system senses virus-induced hypoxic stress to induce cell-intrinsic antiviral responses and limit inflammation.