Human TMEFF1 is a restriction factor for herpes simplex virus in the brain

Yi-Hao Chan (), Zhiyong Liu, Paul Bastard, Noopur 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, Ayse Kartal, Mary L. Hasek, Shuxiang Zhao, Eduardo Garcia Reino, Yoon Seung Lee, Yoann Seeleuthner, Matthieu Chaldebas, Rasheed Bailey, Catherine Vanhulle, Lazaro Lorenzo, Soraya Boucherit, Flore Rozenberg, Nico Marr, Trine H. Mogensen, Mélodie Aubart, Aurélie Cobat, Olivier Dulac, Melike Emiroglu, Søren R. Paludan, Laurent Abel, Luigi Notarangelo, Richard Longnecker, Greg Smith, Lorenz Studer, Jean-Laurent Casanova () and Shen-Ying Zhang ()
Additional contact information
Yi-Hao Chan: The Rockefeller University
Zhiyong Liu: The Rockefeller University
Paul Bastard: The Rockefeller University
Noopur Khobrekar: Sloan Kettering Institute for Cancer Research
Kennen M. Hutchison: Northwestern University Feinberg School of Medicine
Yasuhiro Yamazaki: National Institutes of Health
Qing Fan: Northwestern University Feinberg School of Medicine
Daniela Matuozzo: Imagine Institute
Oliver Harschnitz: Sloan Kettering Institute for Cancer Research
Nacim Kerrouche: The Rockefeller University
Koji Nakajima: The Rockefeller University
Param Amin: Sloan Kettering Institute for Cancer Research
Ahmad Yatim: The Rockefeller University
Darawan Rinchai: The Rockefeller University
Jie Chen: The Rockefeller University
Peng Zhang: The Rockefeller University
Gabriele Ciceri: Sloan Kettering Institute for Cancer Research
Jia Chen: Northwestern University Feinberg School of Medicine
Kerry Dobbs: National Institutes of Health
Serkan Belkaya: The Rockefeller University
Danyel Lee: The Rockefeller University
Adrian Gervais: The Rockefeller University
Kürşad Aydın: Istanbul Medipol University
Ayse Kartal: Selcuk University
Mary L. Hasek: The Rockefeller University
Shuxiang Zhao: The Rockefeller University
Eduardo Garcia Reino: The Rockefeller University
Yoon Seung Lee: The Rockefeller University
Yoann Seeleuthner: Imagine Institute
Matthieu Chaldebas: The Rockefeller University
Rasheed Bailey: The Rockefeller University
Catherine Vanhulle: CHU Rouen Normandie
Lazaro Lorenzo: Imagine Institute
Soraya Boucherit: Imagine Institute
Flore Rozenberg: Cochin Hospital
Nico Marr: Sidra Medicine
Trine H. Mogensen: Aarhus University
Mélodie Aubart: Imagine Institute
Aurélie Cobat: The Rockefeller University
Olivier Dulac: AP-HP
Melike Emiroglu: Selcuk University
Søren R. Paludan: Aarhus University
Laurent Abel: The Rockefeller University
Luigi Notarangelo: National Institutes of Health
Richard Longnecker: Northwestern University Feinberg School of Medicine
Greg Smith: Northwestern University Feinberg School of Medicine
Lorenz Studer: Sloan Kettering Institute for Cancer Research
Jean-Laurent Casanova: The Rockefeller University
Shen-Ying Zhang: The Rockefeller University

Nature, 2024, vol. 632, issue 8024, 390-400

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07745-x

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