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1.
Nature ; 632(8024): 383-389, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39048823

RESUMO

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.


Assuntos
Fatores de Restrição Antivirais , Encéfalo , Herpes Simples , Herpesvirus Humano 1 , Proteínas de Membrana , Neurônios , Internalização do Vírus , Replicação Viral , Animais , Feminino , Humanos , Masculino , Camundongos , Fatores de Restrição Antivirais/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Morte Celular , Sistemas CRISPR-Cas/genética , Herpes Simples/imunologia , Herpes Simples/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Neurônios/virologia , Neurônios/metabolismo , Carga Viral , Nectinas/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Miosina não Muscular Tipo IIB/metabolismo , Interferon Tipo I , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/prevenção & controle , Doenças Neuroinflamatórias/virologia
2.
Nat Biomed Eng ; 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714892

RESUMO

Messenger RNA vaccines lack specificity for dendritic cells (DCs)-the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid-nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines.

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