Variants in TLR3 as well as TRIF, TRAF3, TBK1, IRF3, and NEMO that code for mediators downstream of TLR3, and UNC93B1 that is involved in TLR3 trafficking, all reduce type I interferon signaling and are reported genetic causes of herpes simplex encephalitis (HSE) (224–229). Here, TLR3 is linked to herpes simplex encephalitis.