%0 Journal Article
%T TMEFF1 is a neuron-specific restriction factor for herpes simplex virus.
%A Dai Y
%A Idorn M
%A Serrero MC
%A Pan X
%A Thomsen EA
%A Narita R
%A Maimaitili M
%A Qian X
%A Iversen MB
%A Reinert LS
%A Flygaard RK
%A Chen M
%A Ding X
%A Zhang BC
%A Carter-Timofte ME
%A Lu Q
%A Jiang Z
%A Zhong Y
%A Zhang S
%A Da L
%A Zhu J
%A Denham M
%A Nissen P
%A Mogensen TH
%A Mikkelsen JG
%A Zhang SY
%A Casanova JL
%A Cai Y
%A Paludan SR
%J Nature
%V 632
%N 8024
%D 2024 Aug 24
%M 39048823
%F 69.504
%R 10.1038/s41586-024-07670-z
%X 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.