Herpes simplex encephalitis: pathogenesis and genetic susceptibility

Herpes simplex encephalitis (HSE) is a rare but severe complication of a frequent and mostly benign infection with herpes simplex virus (HSV). Molecular and cellular determinants of HSE are incompletely understood. The rarity of the disease has suggested an increased susceptibility of some subjects to HSV infection. In a few children with HSE, specific defects of the immune innate response have been identified, which impair the interferon (IFN)-α/β and IFN-λ production of fibroblasts and/or neurons infected with HSV and render these cells more permissive to infection. The mutations affect proteins involved in the pathway of IFN induction by stimulation of the Toll-like Receptor 3 (TLR3). The patients' susceptibility to infection is restricted to HSV central nervous system (CNS) invasion, indicating the specific role of TLR3 in CNS protection against viral infection. The incomplete clinical penetrance suggests that other factors (age, infectious dose) are involved in the development of HSE. Numerous experimental studies have then confirmed the major role of the IFN-TLR3 pathway in limiting access of HSV to and/or viral replication in the CNS. The pathogenesis of adult HSE has not been investigated.