Herpes simplex encephalitis due to a mutation in an E3 ubiquitin ligase

Area of Science:

• Immunology
• Genetics
• Neuroscience

Background:

• Herpes simplex virus type 1 (HSV-1) can cause rare, severe encephalitis.
• Genetic factors influencing susceptibility to HSV-1 encephalitis are not fully understood.

Purpose of the Study:

• To investigate the genetic basis of herpes simplex encephalitis in a pediatric patient.
• To characterize the functional impact of a novel WWP2 gene variant on antiviral immunity.

Main Methods:

• Genome-wide genetic analysis to identify variants.
• Utilized induced pluripotent stem cell-derived neural precursor cells and neurons.
• Assessed Toll-like receptor 3 (TLR3) signaling and HSV-1 susceptibility.
• Investigated TRIF ubiquitination and employed CRISPR-Cas9 gene editing.

Main Results:

• Identified a rare heterozygous WWP2 variant (p.R841H) in a patient with HSV-1 encephalitis.
• The p.R841H variant impaired TLR3-mediated signaling and increased neuronal susceptibility to HSV-1.
• This variant enhanced TRIF ubiquitination and reduced antiviral immunity, which was restored by CRISPR-Cas9 correction.

Conclusions:

• The identified WWP2 p.R841H variant is linked to impaired antiviral immunity and increased susceptibility to HSV-1 encephalitis.
• WWP2 plays a crucial role in regulating TLR3-mediated antiviral responses in neural cells.
• This finding highlights a potential genetic predisposition to severe HSV-1 infections.