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

Area of Science:

• Neurovirology
• Human Genetics
• Molecular Biology

Background:

• Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is a severe neurological condition with many unexplained cases.
• Understanding the host factors involved in viral entry into the central nervous system is crucial for developing effective treatments.

Observation:

• Two unrelated individuals with childhood HSE were found to be homozygous for rare, detrimental variants in the TMEFF1 gene.
• TMEFF1 encodes a cell membrane protein highly expressed in brain cortical neurons.

Findings:

• TMEFF1 interacts with the HSV-1 receptor NECTIN-1, inhibiting viral fusion and entry into neurons.
• TMEFF1 deficiency allows rapid HSV-1 entry and replication in cortical neurons, a phenotype rescued by type I interferon or wild-type TMEFF1.
• The extracellular domain of TMEFF1 confers resistance to HSV-1 infection in non-neuronal cells.

Implications:

• Human TMEFF1 functions as a host restriction factor for HSV-1 entry into cortical neurons.
• Inherited TMEFF1 deficiency can predispose individuals to HSE by rendering cortical neurons susceptible to HSV-1.
• This discovery opens new avenues for understanding HSE pathogenesis and potential therapeutic targets.