{Reference Type}: Journal Article
{Title}: TMEFF1 is a neuron-specific restriction factor for herpes simplex virus.
{Author}: Dai Y;Idorn M;Serrero MC;Pan X;Thomsen EA;Narita R;Maimaitili M;Qian X;Iversen MB;Reinert LS;Flygaard RK;Chen M;Ding X;Zhang BC;Carter-Timofte ME;Lu Q;Jiang Z;Zhong Y;Zhang S;Da L;Zhu J;Denham M;Nissen P;Mogensen TH;Mikkelsen JG;Zhang SY;Casanova JL;Cai Y;Paludan SR;
{Journal}: Nature
{Volume}: 632
{Issue}: 8024
{Year}: 2024 Aug 24
{Factor}: 69.504
{DOI}: 10.1038/s41586-024-07670-z
{Abstract}: 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.