Abstract

Herpes simplex encephalitis (HSE) is a rare complication of herpes simplex virus-1 (HSV-1) infection affecting young children as well as adults. Although rare in occurrence, HSE remains the most common cause of acute, sporadic viral encephalitis in the western world. HSE patients are otherwise healthy with no apparent immunodeficiency or increased susceptibly to other viral infections or other forms of HSV -1 infections.

We have hypothesized that at least a subset of patients with HSE , in particular children, are genetically predisposed to HSE due to a specific immunodeficiency in their response to HSV -1 infection. We have now identified mutations in five genes of the TLR3 -IFN pathway leading to impaired TLR3 -dependent induction of interferons in patients with HSE . These patients are unable to control HSV1 replication in fibroblasts however their antiviral response in PBM Cs are normal, consistent with the CNS -restricted and HSV -1-restricted infectious phenotype in these children, who are otherwise normally resistant to other infections.

HSE provides proof-of-principle that a collection of single-gene variations displaying incomplete penetrance at the clinical level and affecting different, but immunologically related genes, may account for severe, sporadic and common infectious diseases of childhood.