Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 390-400 |
| Number of pages | 11 |
| Journal | Nature |
| Volume | 632 |
| Issue number | 8024 |
| DOIs | |
| State | Published - Aug 8 2024 |
Funding
We thank the patients and their families; members of both branches of the Laboratory of Human Genetics of Infectious Diseases for discussions; T. Kochetkov for technical assistance; and Y. Nemirovskaya and E. Williams for administrative assistance. This work was conducted in the two branches of the Laboratory of Human Genetics of Infectious Diseases. The work was funded in part by the National Center for Advancing Translational Sciences; the US National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) programme (UL1TR001866); the Stavros Niarchos Foundation (SNF) as part of its grant to the SNF Institute for Global Infectious Disease Research at The Rockefeller University; the Shapiro\u2013Silverberg Fund for the Advancement of Translational Research; NIH grants (R01AI088364 and R01NS072381 and by core grant P30CA008748); the Starr Foundation Tri-Institutional Stem Cell Initiative (2021-019); the Robertson Therapeutic Development Fund; grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX\u221262-IBEID) and the French National Research Agency (ANR) under the \u2018Investments for the future\u2019 programme (ANR-10-IAHU-01), and the ANR grants IEIHSEER (ANR-14-CE14-0008-01), SEAeHostFactors (ANR-18-CE15-0020-02) and CNSVIRGEN (ANR-19-CE15-0009-01). We thank W. E. Ford (General Atlantic); G. Caillaux (General Atlantic); the General Atlantic Foundation; the Rockefeller University; the Howard Hughes Medical Institute; INSERM; Paris Cit\u00E9 University; Imagine Institute; and the St. Giles Foundation for their general support to the works performed in the Laboratory of Human Genetics of Infectious Diseases. S.R.P. was funded by the European Research Council (786602), the Novo Nordisk Foundation (NNF18OC0030274, NNF20OC0064301), the Lundbeck Foundation (R359-2020-2287), the Danish National Research Foundation (DNRF164) and the Swedish Research Council (2021-00942). The Longnecker laboratory is funded by NIH grant R01AI14878-04. We thank P. Banerjee (the Rockefeller University Bio-Imaging Resource Center, RRID:SCR_017791) for assistance with confocal imaging. Y.-H.C. is supported by an A*STAR International Fellowship (AIF). P.B. was supported by the French Foundation for Medical Research (EA20170638020), the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller) and the Poste CCA-INSERM-Bettencourt (with the support of the Fondation Bettencourt-Schueller). A.Y. was supported by fellowships from the European Academy of Dermatology and Venereology and the Swiss National Science Foundation, and by an early career award from the Thrasher Research Fund. D.L. was supported by a fellowship from the French Foundation for Medical Research for medical residents and fellows and the ESID 2023 Juniors Bridge Grant.
ASJC Scopus subject areas
- General