The induction of type I interferon (IFN /) is necessary for the stimulation of effective anti-viral and anti-tumor host defense. IFN can be activated by numerous pathogens and exerts multipleotropic effects through the induction of numerous genes which can invoke a cellular anti-viral effect or stimulate the activity of natural killer (NK) and dendritic cell (DC) subsets. DsRNA 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). However, it has recently become apparent that TLR-independent, intracellular mechanisms of dsRNA recognition and signal transduction alternatively exist to induce type I IFN. These processes have been reported to involve FADD (Fas associated with death domain) and RIP1 (receptor interacting protein kinase 1), which are required for the activation of NF-B and IRF-3 (transcription factors necessary for the induction of IFN). The upstream cellular signaling molecules required for interacting with dsRNA and modulating the activity of FADD/RIP1 remained undefined. However, it has recently been reported that the DExD/H box RNA helicases, RIG-I (Retinoic acid inducible gene-I) and MDA5 (melanoma differentiation antigen 5) are key players in recognizing viral dsRNA species and triggering innate immune responses. Importantly, ours and others data confirm that FADD/RIP is required to facilitate DExD/H box-mediated signaling. Given this data, our objectives here are to delineate the post-translational mechanisms of innate immune signaling that appear to require FADD and RIP1 to exert innate signaling activity. Understanding how these pathways function has significant impact on understanding pathogenesis and for developing novel therapeutics and vaccines to combat disease.
The cell has adapted to respond to pathogen infection by triggering the production of proteins which prevent infection. This proposal intends to unravel the mechanisms of anti-viral host defense, an investigation which may shed light into the causes of pathogenesis and may lead to the development of new therapeutics to combat disease.
