Human TMEFF1 is a restriction factor for herpes simplex virus in the brain.
Клинический случайСтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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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, Aydın Kürşad, 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 Mélodie, Cobat Aurélie, Dulac Olivier, Emiroglu Melike, Paludan Søren R, Abel Laurent, Notarangelo Luigi, Longnecker Richard, Smith Greg, Studer Lorenz, Casanova Jean-Laurent, Zhang Shen-Ying
Аннотация
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.