Browsing by Author "Kerrouche, Nacim"

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    Human TMEFF1 is a restriction factor for herpes simplex virus in the brain
    (NATURE PORTFOLIO, 2024-07) Chan, Yi-Hao; Liu, Zhiyong; Bastard, Paul; Khobrekar, Noopur; Hutchison, Kennen M.; Yamazaki, Yasuhiro; Fan, Qing; Matuozzo, Daniela; Harschnitz, Oliver; Kerrouche, Nacim; Nakajima, Koji; Amin, Param; Yatim, Ahmad; Rinchai, Darawan; Chen, Jie; Zhang, Peng; Ciceri, Gabriele; Chen, Jia; Dobbs, Kerry; Belkaya, Serkan; Lee, Danyel; Gervais, Adrian; Aydin, Kuersad; Kartal, Ayse; Hasek, Mary L.; Zhao, Shuxiang; Reino, Eduardo Garcia; Lee, Yoon Seung; Seeleuthner, Yoann; Chaldebas, Matthieu; Bailey, Rasheed; Vanhulle, Catherine; Lorenzo, Lazaro; Boucherit, Soraya; Rozenberg, Flore; Marr, Nico; Mogensen, Trine H.; Aubart, Melodie; Cobat, Aurelie; Dulac, Olivier; Emiroglu, Melike; Paludan, Soren R.; Abel, Laurent; Notarangelo, Luigi; Longnecker, Richard; Smith, Greg; Studer, Lorenz; Casanova, Jean-Laurent; Zhang, Shen-Ying
    Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE. A study of two childhood cases of herpes simplex encephalitis shows that TMEFF1 interacts with the HSV-1 cell-surface receptor NECTIN-1, preventing HSV-1 from fusing with the cell membrane and entering cortical neurons.