Innate Intracellular Mechanisms

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DESCRIPTION (provided by applicant): Viral RNA species are known to be inadvertent, potent inducers of type I IFN, following interaction with extracellular receptors such as toll-like receptor 3 (TLR 3). Recently, it has become apparent from work done by our group and others that TLR-independent, intracellular mechanisms of dsRNA recognition and host defense signal transduction alternatively exist to induce type I IFN required to thwart virus infection. These processes have been reported to involve related helicases referred to as RIG-I, MDA5 and LGP2, which putatively function as intracellular receptors which recognize virus infection and trigger the production of type I IFN. RIG-I reportedly recognizes negative stranded viruses, while MDA5 recognizes positive stranded viruses. LGP2 function, however, remains to be clarified. Our data has confirmed that FADD (Fas associated with death domain) and RIP1 (Receptor interacting protein kinase 1), are necessary for efficient RIG-I/MDA5 function and the activation of NF-kappaB and IRF-3 (transcription factors necessary for the induction of IFN). The requirement for FADD/RIP1 in mammalian host defense is evocative of innate immune pathways in Drosophila, referred to as the IMD pathway, which utilizes a dFADD-dependent signaling cascade that responds to infection by activating the transcription of anti-microbial genes. These data therefore suggest the existence of a conserved pathogen recognition pathway that, in mammalian cells, is central for the induction of type I IFN and other genes important for host defense. Given this data, we intend for this proposal, to further delineate the mechanisms of innate immune signaling. This will include the following objectives: We have developed a viable murine model that lacks LGP2 and will examine the importance of this helicase in innate immune responses to virus infection. This study will include evaluating the role of the dsRNA transducing molecules MDA5 and RIG-I in innate signaling events, including potential regulation by LGP2. We aim to further characterize the role of FADD and RIP1 in innate signaling processes, including role in RIG-I and NDA5 mediated signaling. This study will involve the role of post-translational modification events in FADD function. We have isolated a new molecule, STING, that is a potent inducer of IFN Signaling and that requires FADD for efficient activity. The importance of STING in innate signaling will be determined. Understanding how these pathways function has significant impact on understanding pathogenesis and for developing novel therapeutics and vaccines to combat disease.