I-FIVE · Interferon-focused Innate Immunity Interactome and Inhibitome

After a decade of development in model organisms and later in mammalian cells, mass spectrometry-based functional proteomics approaches have come of age and are ready to enable a systematic study of the innate immune system. We propose to cross the large-scale proteomics and innate immunity disciplines to obtain a functionally annotated map of the molecular machinery involved in viral recognition and leading to the hallmark interferon response, through a three-pronged approach: 1. Map the interactome of innate immunity proteins in macrophages to establish the network of components leading to interferon production; 2. Chart the interactions of molecular patterns, mostly nucleic acids, to identify the receptors and sensors at the non-self/self interface; 3. Study viral pathogenicity factors as molecular jammers of the anti-viral response and elucidate their mode of action to uncover critical nodes (inhibitome). Datasets are integrated and released at regular intervals with embargoed windows allowing a network of collaborators/own laboratory to do in-depth validation. New components at data intersections will be tested through loss-of-function experiments and standardized read-outs for the interferon pathway as well as genetic association with autoimmune diseases. Because of its unbiased/large scope and its cross-validating approaches, wherein the newly mapped circuitry is modeled, challenged by inducers and perturbed by viral agents, i-FIVE has the potential to promote a systems-level understanding of the interferon branch of molecular innate immunity. This insight may in turn create medical opportunities for the treatment of autoimmune disorders, septic shoc, arthritis as well as in boosting anti-viral responses.