A number of seminal discoveries by Casanova and colleagues described an essential non-redundant role of TLR3 signaling, including TLR3, UNC93B, TRIF, TRAF3, and TBK1, and the generation of type I IFN responses in the central nervous system (CNS) in protection against herpes simplex encephalitis (HSE) (33–37). The gene discussed is TRAF3; the disease is herpes simplex encephalitis.