Final Report Summary - I-FIVE (Interferon-focused Innate Immunity Interactome and Inhibitome) Innate immune processes are very much centered on the management of molecular interactions. A variety of activities demand it: Detection of pathogens and danger signals, distinction of self- from non-self molecules, signaling to initiate cellular responses, neutralization of pathogens, resolution of infection and inflammation. In the dynamic course of innate immune responses, one can roughly distinguish between a first alarm-calling phase leading to the secretion of type I interferons and pro-inflammatory cytokines and a response and execution phase during which pathogens are neutralized, presented to cells of the adaptive immune system, and the alarm is switched off. The Interferon-focused Innate Immunity Interactome and Inhibitome project, short i-FIVE (a pun on the celebratory hand gesture), set off to map the uncharted innate immunity networks in five years. The i-FIVE team has produced important results, published prominently for instance in the journals Nature, Cell, Nature Immunology and in the open access journal PLOS ONE. Using affinity proteomics coupled to mass spectrometry and bioinformatics (essentially a sophisticated molecular “fishing”), but also functional assays like infections with the relevant viruses after gene inactivation, they have step-wise mapped these networks and determined how viruses can manipulate them. Moreover, they have characterized the dynamic assembly, disassembly and regulation of several host molecular machines able to counteract viral attacks. Among the things learned is that viruses have found very interesting ways to circumvent the cellular detection and alarm system, including a strategy aimed at undermining communication among the different parts of the cellular “factory”. This way, imbalances challenging cellular homeostasis (for example proteostatic processes, quorum-sensing mechanisms, integration processes) may fail to cause stress and alarm. From the cellular machinery point-of-view the team has been further focusing on membrane and organelle transport, nutrient sensing and lipid homeostasis. A great deal of interesting follow-up projects are under way.
