Functional IRF3 deficiency in a patient with herpes simplex encephalitis

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Herpes simplex encephalitis (HSE) in children is often associated with impaired type I interferon (IFN) production.
• Toll-like receptor 3 (TLR3) pathway defects have been previously implicated in HSE pathogenesis.

Purpose of the Study:

• To identify novel genetic causes of HSE.
• To investigate the role of interferon regulatory factor 3 (IRF3) in susceptibility to HSE.

Main Methods:

• Genetic analysis of a patient with HSE to identify causative mutations.
• Functional studies of the identified IRF3 mutation in patient fibroblasts.
• Assessment of IFN production and signaling pathways in response to HSV-1 infection.

Main Results:

• A heterozygous loss-of-function mutation (R285Q) in the IRF3 gene was identified in an adolescent female patient with HSE.
• This mutation leads to autosomal dominant IRF3 deficiency by haploinsufficiency.
• The R285Q mutation impairs IRF3 activation, phosphorylation, dimerization, and subsequent induction of type I IFN, particularly through the TLR3-TRIF pathway.
• Patient fibroblasts expressing the mutant IRF3 showed reduced IFN production in response to HSV-1 infection, which was rescued by wild-type IRF3 transduction.

Conclusions:

• This study identifies IRF3 deficiency as a novel genetic etiology of HSE.
• It highlights the critical role of IRF3 in the innate immune response against HSV-1 in the central nervous system.
• This finding represents the first description of a defect in an IFN-regulating transcription factor conferring susceptibility to viral CNS infections in humans.