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

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 () and Søren R. Paludan ()
Additional contact information
Yao Dai: Shanghai Jiao Tong University
Manja Idorn: Aarhus University
Manutea C. Serrero: Aarhus University
Xiaoyong Pan: Shanghai Jiao Tong University
Emil A. Thomsen: Aarhus University
Ryo Narita: Aarhus University
Muyesier Maimaitili: Aarhus University
Xiaoqing Qian: Shanghai Jiao Tong University
Marie B. Iversen: Aarhus University
Line S. Reinert: Aarhus University
Rasmus K. Flygaard: Aarhus University
Muwan Chen: Aarhus University
Xiangning Ding: Aarhus University
Bao-cun Zhang: Aarhus University
Madalina E. Carter-Timofte: Aarhus University
Qing Lu: Shanghai Jiao Tong University
Zhuofan Jiang: Shanghai Jiao Tong University
Yiye Zhong: Shanghai Jiao Tong University
Shuhui Zhang: Shanghai Jiao Tong University
Lintai Da: Shanghai Jiao Tong University
Jinwei Zhu: Shanghai Jiao Tong University
Mark Denham: Aarhus University
Poul Nissen: Aarhus University
Trine H. Mogensen: Aarhus University
Jacob Giehm Mikkelsen: Aarhus University
Shen-Ying Zhang: Imagine Institute
Jean-Laurent Casanova: Imagine Institute
Yujia Cai: Shanghai Jiao Tong University
Søren R. Paludan: Aarhus University

Nature, 2024, vol. 632, issue 8024, 383-389

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07670-z

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