Innate immune signalling platform formation in infection and inflammation

Pattern Recognition Receptor (PRR) activity helps control infections, but dysregulated PRR activity causes the chronic inflammation that underpins many diseases. PRRs signal through forming oligomeric supramolecular organizing centres (SMOCs), such as the MyDDosome, TRIFosome or inflammasomes. We pioneered the application of novel imaging tools to define how PRRs signal in cells and we have begun to understand these processes, but most available data is based on overexpression systems rather than the native SMOC proteins themselves. Recent studies by us, and others, using endogenously tagged PRR-SMOC components reveal unexpected structural transitions in SMOC formation which dictate functional outputs. Our new data suggests activation of the adaptor protein Toll/IL-1R domain-containing adaptor-inducing interferon-β (TRIF), for example, first signals from small TRIF complexes to drive interferon signalling, but later large TRIF clusters (TRIFosomes) form to support nuclear factor kappa B signalling. MyDDosomes and inflammasomes also form small signalling complexes which progress to large SMOCs with a potential myriad of functions suggesting this is a common mechanism in PRR signalling. Here we will investigate why large SMOCs form, how are they organised and regulated, what protein-protein interactions occur to direct signalling outcomes and whether selective inhibition can be achieved to develop novel therapeutic interventions.