Article Dans Une Revue Nature Année : 2024

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

Yi-Hao Chan
Kennen Hutchison
  • Fonction : Auteur
Yasuhiro Yamazaki
  • Fonction : Auteur
Param Amin
  • Fonction : Auteur
Serkan Belkaya
  • Fonction : Auteur
Kürşad Aydın
  • Fonction : Auteur
Ayse Kartal
  • Fonction : Auteur
Mary Hasek
  • Fonction : Auteur
Shuxiang Zhao
  • Fonction : Auteur
Eduardo Garcia Reino
Yoon Seung Lee
Matthieu Chaldebas
Rasheed Bailey
  • Fonction : Auteur
Catherine Vanhulle
  • Fonction : Auteur
Nico Marr
  • Fonction : Auteur
Trine Mogensen
Melike Emiroglu
Søren Paludan
Luigi Notarangelo
Richard Longnecker
Greg Smith
Lorenz Studer

Résumé

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained 1,2 . 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.

Dates et versions

hal-04926936 , version 1 (03-02-2025)

Identifiants

Citer

Yi-Hao Chan, Zhiyong Liu, Paul Bastard, Noopur Khobrekar, Kennen Hutchison, et al.. Human TMEFF1 is a restriction factor for herpes simplex virus in the brain. Nature, 2024, 632 (8024), pp.390-400. ⟨10.1038/s41586-024-07745-x⟩. ⟨hal-04926936⟩
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