Human TMEFF1 is a restriction factor for herpes simplex virus in the brain Journal Article
| Authors: | Chan, Y. H.; Liu, Z. Y.; Bastard, P.; Khobrekar, N.; Hutchison, K. M.; Yamazaki, Y.; Fan, Q.; Matuozzo, D.; Harschnitz, O.; Kerrouche, N.; Nakajima, K.; Amin, P.; Yatim, A.; Rinchai, D.; Chen, J.; Zhang, P.; Ciceri, G.; Chen, J.; Dobbs, K.; Belkaya, S.; Lee, D.; Gervais, A.; Aydin, K.; Kartal, A.; Hasek, M. L.; Zhao, S. X.; Reino, E. G.; Lee, Y. S.; Seeleuthner, Y.; Chaldeba, M.; Bailey, R.; Vanhulle, C.; Lorenzo, L.; Boucherit, S.; Rozenberg, F.; Marr, N.; Mogensen, T. H.; Aubart, M.; Cobat, A.; Dulac, O.; Emiroglu, M.; Paludan, S. R.; Abel, L.; Notarangelo, L.; Longnecker, R.; Smith, G.; Studer, L.; Casanova, J. L.; Zhang, S. Y. |
| Article Title: | Human TMEFF1 is a restriction factor for herpes simplex virus in the brain |
| Abstract: | 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. |
| Keywords: | encephalitis; expression; transmembrane protein; nectin-1; entry; tlr3 deficiency; inborn-errors; neuron-intrinsic immunity; glycoprotein-d; tomoregulin-1 |
| Journal Title: | Nature |
| Volume: | 632 |
| Issue: | 8024 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-08-08 |
| Start Page: | 390 |
| End Page: | 400 |
| Language: | English |
| ACCESSION: | WOS:001276265800012 |
| DOI: | 10.1038/s41586-024-07745-x |
| PROVIDER: | wos |
| PMCID: | PMC11306101 |
| PUBMED: | 39048830 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Wos |
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