The focus of this Project is to define the virus-host interactions that trigger and control innate immunity against flavivirus infection. Innate immunity represents are our first line of immune defense against viruses, and we have found that type I interferon actions and specific innate immune programs that operate independently of the cellular transcription factors, interferon regulatory factor-3 and -7, play major roles to control West Nile virus (WNV) infection. WNV is an emerging virus agent that has rapidly spread throughout the Western hemisphere since its introduction to New York in late 1999. WNV is now a leading cause of encephalitis and is observed to causes death at an increased rate over the past decade. The Aims of this project include major goals to: Aim 1) Define the IRF-3/IRF-7-independent program of innate antiviral defenses against WNV infection; and Aim 2: Define the pathways and actions of type I interferon signaling of innate immune defenses that control WNV infection and determine the mechanism by which pathogenic WNV antagonizes the host cell interferon response. These studies will deliver novel therapeutic targets for strategies to modulate immunity to infection.