HSV-1 detection by innate immunity. The innate immune system recognizes HSV-1 using different PRRs. Viral glycoproteins H and L are sensed by TLR2, while soluble gD activates HVEM. Viral DNA is recognized by TLR9 localized in the endolysosome or activates DAI, cGAS, and IFI16 localized in the cytoplasm. Viral dsRNA, a replication byproduct, enters the cells from the extracellular environment following the breakdown of infected cells. The dsRNA activates TLR3 in the endolysosome or cytoplasmic receptors, RIG-I, and MDA5, as well as PKR. RIG-I and MDA5 signal via the adaptor mitochondrial antiviral-signaling protein (MAVS) localized at the mitochondrion. The appropriate adaptor proteins are used to govern TLRs signaling pathways: TLR3 signaling utilizes TRIF while TLR2 and TLR9 exploit MYD88. The execution of signaling pathways, shown by the dashed lines, leads to the activation of transcription factors, such as the interferon regulatory factor 3 (IRF3), IRF7 and nuclear factor kappa B (NF-κB), which enter the nucleus and trigger the expression of proinflammatory cytokines and type I IFNs.