TMEFF1 is a neuron-specific restriction factor for herpes simplex virus

• 成果类型: Article
• 署名作者: Dai, Yao; Idorn, Manja; Serrero, Manutea C.; Pan, Xiaoyong; Thomsen, Emil A.; Narita, Ryo; Maimaitili, Muyesier; Qian, Xiaoqing; Iversen, Marie B.; Reinert, Line S.; Flygaard, Rasmus K.; Chen, Muwan; Ding, Xiangning; Zhang, Bao-cun; Carter-Timofte, Madalina E.; Lu, Qing; Jiang, Zhuofan; Zhong, Yiye; Zhang, Shuhui; Da, Lintai; Zhu, Jinwei; Denham, Mark; Nissen, Poul; Mogensen, Trine H.; Mikkelsen, Jacob Giehm; Zhang, Shen-Ying; Casanova, Jean-Laurent; Cai, Yujia; Paludan, Soren R.
• 署名单位: Shanghai Jiao Tong University; Aarhus University; Shanghai Jiao Tong University; Shanghai Jiao Tong University; Aarhus University; Aarhus University; Shanghai Jiao Tong University; Aarhus University; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Rockefeller University; Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Necker-Enfants Malades - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Howard Hughes Medical Institute; University of Gothenburg
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5039
• DOI: 10.1038/s41586-024-07670-z
• 发表日期: 2024-08-08
• 页码: 383-+
• 关键词: inborn-errors; receptor; protein; entry; rna; deficiency; mutations; deletion; immunity; vectors

摘要

The brain is highly sensitive to damage caused by infection and inflammation(1,2). Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis(3). 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, respectively(4-6). 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.