Type I interferon (IFN) provides an initial component of innate immune resistance to viral infection and replication by inducing a large set of antiviral effector proteins capable of inhibiting diverse viruses at multiple points in the infection. Inherent to the effectiveness of this response are cellular signaling pathways that first trigger IFN gene induction in response to infection and subsequently trigger IFN-stimulated gene (ISG) expression in response to secreted IFN. IFN gene induction proceeds through two distinct pathways, a cytosolic signaling system triggered by viral nucleic acid in the cytoplasm that operates in most infected cells and a transmembrane pathway dependent on Toll-like receptor (TLR) proteins that is critical in dendritic cells. The essential nature of the IFN system in antiviral immunity has been demonstrated by genetic and biochemical data, but its ultimate effectiveness is limited by viral evasion through the action of viral virulence factors that impaire IFN action. The underlying hypothesis of our proposed research is that through better understaning the molecular mechanisms of IFN induction and action and their impairment by viral evasion, we will be able to devise novel therapeutics based on augmenting innate immunity and inhibiting viral evasion. This project focuses on three distinct viruses that each impair the IFN pathway, influenza A virus, vaccinia virus, and chikungunya virus; will analyze the interaction between viruses and IFN signaling in a unique set of genetically modified dendritic cells lines; and will develop a platform to screen for small molecule inhibitors of viral virulence. This work will be performed in close collaboration with other members of the innate immunity team, Drs. Easier, Garcia-Sastre, and Wu. This project is well integrated into the mission of the RCE. Innate immunity has emerged as an essential component of the key focus areas of the RCE, impacting on adaptive immunity and being critical for athe adjuvant effects of vaccines; providing an important diagnostic indication of infection; and uncovering a novel approach to therapeutics by targeting the interaction between the innate immune system and virulence factors. Knowledge gained in these studies will also be applicable to microbial innate immunity that relies on similar mechanisms.