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

• 成果类型: Article
• 署名作者: 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, Kursad; Kartal, Ayse; Hasek, Mary L.; Zhao, Shuxiang; Reino, Eduardo Garcia; Lee, Yoon Seung; Seeleuthner, Yoann; Chaldeba, 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
• 署名单位: Rockefeller University; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Northwestern University; Feinberg School of Medicine; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Human Technopole; Ihsan Dogramaci Bilkent University; Istanbul Medipol University; Selcuk University; Universite de Rouen Normandie; CHU de Rouen; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Cochin - APHP; Sidra Medical & Research Center; Aarhus University; Aarhus University; Aarhus University; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Selcuk University; University of Gothenburg; Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5346
• DOI: 10.1038/s41586-024-07745-x
• 发表日期: 2024-08-08
• 页码: 390-+
• 关键词: neuron-intrinsic immunity; tlr3 deficiency; transmembrane protein; glycoprotein-d; inborn-errors; encephalitis; nectin-1; tomoregulin-1; expression; entry

摘要

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.