In the present study, we demonstrated and concluded (i) based on the data of Otsuki et al., that Nrf2AY/AY mutant macrophages displayed a profound dysregulation of the antiviral gene expression profile compared to WT murine cells, (ii) that Nrf2 impaired the response to herpes virus-derived dsDNA without affecting STING expression in murine cells, (iii) that the genetic activation of Nrf2 increased HSV-2 replication in vitro, and (iv) that Nrf2−/− mice are less susceptible to vaginal infection with HSV-2 due to heightened type I IFN response. The gene discussed is NFE2L2; the disease is infective vaginitis.