IRF7 and UNC93B1 variants in an infant with recurrent herpes simplex virus infection

Area of Science:

• Immunology
• Genetics
• Virology

Background:

• Neonatal herpes simplex virus (HSV) infection causes severe disease, but its genetic basis is poorly understood.
• Susceptibility to HSV in newborns requires further investigation into underlying genetic factors.

Observation:

• A male infant experienced neonatal skin/eye/mouth (SEM) HSV-1 disease, followed by HSV-1 encephalitis at one year of age.
• Immune workup revealed an anergic peripheral blood mononuclear cell (PBMC) cytokine response specifically to Toll-like receptor 3 (TLR3) stimulation.
• Exome sequencing identified rare missense variants in IFN-regulatory factor 7 (IRF7) and UNC-93 homolog B1 (UNC93B1).

Findings:

• Single-cell RNA sequencing of PBMCs showed reduced innate immune gene expression and a repressed TLR3 pathway signature in multiple cell types, including CD14 monocytes.
• In vitro studies demonstrated that both IRF7 and UNC93B1 variants suppressed TLR3-driven IRF3 activity and type I interferon response.
• Fibroblasts with these variants exhibited increased intracellular HSV-1 titers and a blunted type I interferon response upon HSV-1 challenge.

Implications:

• This study identifies deleterious variants in IRF7 and UNC93B1 associated with recurrent, severe HSV-1 disease and encephalitis.
• Mutations in the TLR3 pathway may predispose neonates to severe and recurrent HSV infections.
• Understanding these genetic underpinnings can inform diagnosis and management of severe neonatal HSV disease.