In 2 unrelated French children with herpes simplex encephalitis (HSE) but no UNC93B (608204) deficiency, Zhang et al. (2007) detected a heterozygous pro554-to-ser (P554S; 603029.0001) mutation in the TLR3 gene. The mutation occurred on different TLR3 haplotypes in ... In 2 unrelated French children with herpes simplex encephalitis (HSE) but no UNC93B (608204) deficiency, Zhang et al. (2007) detected a heterozygous pro554-to-ser (P554S; 603029.0001) mutation in the TLR3 gene. The mutation occurred on different TLR3 haplotypes in the children. Stimulation of heterozygous dermal fibroblasts or monocyte-derived dendritic cells with polyinosinic:polycytidylic acid (poly(I:C)), but not lipopolysaccharide, showed hyporesponsiveness in patient cell lines that could be reversed by transfection of wildtype TLR3. Infection with HSV-1, or vesicular stomatitis virus, but not other viruses, resulted in weaker IFNB (147640) and IFNL (IL29; 607403) production and increased viral replication in heterozygous TLR3-deficient fibroblasts. Myeloid and plasmacytoid dendritic cells, however, responded normally to poly (I:C), possibly explaining why HSE is a non-blood-borne viral encephalitis. Zhang et al. (2007) proposed that TLR3 is vital for natural immunity to HSV-1 in the central nervous system and suggested that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.