Modification of TLR signaling is a promising strategy for treatment of cancer, allergy, and infectious diseases [64, 65] . Especially, the immunomodulators should not generate resistant virus to drugs compared to antiviral drugs targeting viral proteins. As an existing example of virus infection, imiquimod, which is a TLR7 agonist, have been applied to an infectious disease caused by human papilloma virus, namely, condylomata acuminata [66] . TLR4 antagonists are trying to be applied to treatment of sepsis. Several issues must be considered for the clinical application of TLR signaling. Among the greatest is assessment of what are keys of host defense or virus survival in view of a series of viral infection process. For example, human herpes simplex virus 1 (HSV-1) requires activated NF-κB for its efficient replication [67] . On the other hand, NF-κB has a key role in inflammatory reactions via transcription activation of proinflammatory cytokines, cell adhesion molecules, and MHC. Thus, activation of NF-κB is a double-edged sword for HSV-1. In the host side, TLR signaling varies according to organs and tissues. For example, intestinal epithelial cells express low levels of TLRs and high levels of negative regulators of TLR signaling, such as Tollip [68, 69] . Also, in intestinal immunity, NF-κB activation in a subset TLR signaling in DCs and macrophages is suppressed by a negative regulation IκBNS [70] . The dysregulation of TLR signaling in the lumen of intestinal epithelial causes limit chronic inflammatory activation induced by commensal bacteria. Various TLR polymorphisms have been found, and some of them are shown to contribute to dysregulation of TLR signaling. The dysregulation has been suggested to be linked with a number of disease sensitivity and condition depending on individual differences [71, 72] .