Human TMEFF1 is a restriction factor for herpes simplex virus in the brain
Yi‐Hao Chan, Zhiyong Liu, Paul Bastard, Noopur V. Khobrekar, Kennen M. Hutchison, Yasuhiro Yamazaki, Qing Fan, Daniela Matuozzo, Oliver Harschnitz, Nacim Kerrouche, Koji Nakajima, Param Amin, Ahmad Yatim, Darawan Rinchai, Jie Chen, Peng Zhang, Gabriele Ciceri, Jia Chen, Kerry Dobbs, Serkan Belkaya, Danyel Lee, Adrian Gervais, Kürşad Aydın, Ayşe Kartal, Mary L. Hasek, Shuxiang Zhao, Eduardo J. Garcia Reino, Yoon Seung Lee, Yoann Seeleuthner, Matthieu Chaldebas, Rasheed Bailey, C. Vanhulle, Lazaro Lorenzo, Soraya Boucherit, Flore Rozenberg, Nico Marr, Trine H. Mogensen, Mélodie Aubart, Aurélie Cobat, Olivier Dulac, Melike Emiroğlu, Søren R. Paludan, Laurent Abel, Luigi D. Notarangelo, Richard Longnecker, Gregory A. Smith, Lorenz Studer, Jean‐Laurent Casanova, Shen‐Ying Zhang
Abstract
. 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.