Human TMEFF1 is a restriction factor for herpes simplex virus in the brain.
Nature
; 632(8024): 390-400, 2024 Aug.
Article
in En
| MEDLINE
| ID: mdl-39048830
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Herpesvirus 1, Human
/
Encephalitis, Herpes Simplex
/
Virus Internalization
/
Membrane Proteins
Limits:
Adult
/
Animals
/
Child, preschool
/
Female
/
Humans
/
Male
Language:
En
Journal:
Nature
Year:
2024
Type:
Article
Affiliation country:
United States