The innate immune system uses a multitude of receptors to sense pathogens and danger signals. Upon their activation, a signalling cascade is initiated culminating in the transcription and translation of cytokines and other proteins vital for host protection. Recent studies have discovered that an array of these intracellular signalling proteins assemble into oligomeric signalling platforms, consequently amplifying the transmission of the signal.Unexpectedly, it was also discovered that some of these proteins such as the adaptor proteins ASC and MAVS, can form fibrils, that elongate in a prion-like manner to create super-sized signalling platforms.In this study, we screened over 100 innate immune intracellular signalling proteins using single molecule fluorescence. In defining the oligomerisation/aggregation propensity of these proteins, we identified multiple candidates forming super-sized protein aggregates, concluding that ~20 of these proteins could self-propagate aggregation as found in prion-like mechanisms.These innate immune cytosolic proteins transverse most, if not all, signalling pathways. Intriguingly, some of these proteins could act to regulate/inhibit the signalling cascade through their prion-like protein propagation. Through focusing in on each pathway, their protein-protein interactions and disease-associated point mutations, we are delineating the diverse networks of signalling proteins that drive and regulate inflammation and innate immune defense, as well as cell death. Thus, aiding in elucidating the etiology of the diseases associated with these point mutations such as those of cancer-causing mutation L252P in TLR signalling adaptor protein, MyD88.Our observations suggest that prion-like polymerization underlies the backbone of intracellular communication and drives the complex interplay that exists among the major signalling cascades of the innate immune system. Our disease-associated mutagenesis data highlights the crucial functions that these large signalling platforms have in the optimal execution of defense against pathogens and intracellular homeostasis and will contribute to the development of novel therapies aimed at regulating this critical first line of defence.