TMEFF1 Is A Neuron-specific Restriction Factor for Herpes Simplex Virus

Nature  ·  2024  ·  Impact 3

Yao Dai; Manja Idorn; Manutea C Serrero; Xiaoyong Pan; Emil A Thomsen; Ryo Narita; Muyesier Maimaitili; Xiaoqing Qian; Marie B Iversen; Line S Reinert; Rasmus K Flygaard; Muwan Chen; Xiangning Ding; Bao-Cun Zhang; Madalina E Carter-Timofte; Qing Lu; Zhuofan Jiang; Yiye Zhong; Shuhui Zhang; Lintai Da; Jinwei Zhu; Mark Denham; Poul Nissen; Trine H Mogensen; Jacob Giehm Mikkelsen; Shen-Ying Zhang; Jean-Laurent Casanova; Yujia Cai; Søren R Paludan;

RELATED

Papers      Patents     Grants     Venues     Experts    Cite    Share    Save

ABSTRACT

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

 Paraphrase     Questionfy     Wikify     Simplify     Summarize