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

Chan Y., Liu Z., Bastard P., Khobrekar N., Hutchison K. M., Yamazaki Y., ...Daha Fazla

Nature, cilt.632, sa.8024, ss.390-400, 2024 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 632 Sayı: 8024
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1038/s41586-024-07745-x
  • Dergi Adı: Nature
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, International Bibliography of Social Sciences, Aerospace Database, Agricultural & Environmental Science Database, Animal Behavior Abstracts, Applied Science & Technology Source, Aqualine, Aquatic Science & Fisheries Abstracts (ASFA), Art Source, Artic & Antarctic Regions, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Communication Abstracts, EBSCO Education Source, Environment Index, Food Science & Technology Abstracts, Gender Studies Database, Geobase, INSPEC, MEDLINE, Metadex, MLA - Modern Language Association Database, Pollution Abstracts, Psycinfo, Public Affairs Index, Veterinary Science Database, zbMATH, DIALNET, Civil Engineering Abstracts
  • Sayfa Sayıları: ss.390-400
  • İstanbul Medipol Üniversitesi Adresli: Evet

Özet

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.