Final Report Summary - RNAI VS IFN (The interplay between innate immunity and RNA interference in mammals) Plants and invertebrates defend themselves against viral pathogens using a mechanism called RNA interference (RNAi), which is triggered by based-paired or long double-stranded (ds) RNA generated during virus infection. In contrast, it is debated whether this antiviral mechanism acts in vertebrates in which viral RNAs induce a distinct defence system known as the type 1 interferon (IFN) response. Our study demonstrates that long dsRNA-mediated RNAi (dsRNAi) is functionally active in mammalian differentiated cells, yet is inhibited or masked by the IFN pathway. Consistent with that notion, dsRNAi was revealed in IFN-defective cells and relied on canonical components of the RNAi pathway. Notably, dsRNAi specifically vaccinates cells against subsequent infection with viruses containing homologous sequences. Our data suggest that RNAi constitutes an ancient antiviral strategy that has been preserved during the evolution of vertebrate immunity and reveal another set of weapons that mammalian cells have at its disposal to attack viruses. It opens up new avenues of research aiming at understanding in which cell types and contexts this ancestral mechanism play a role as an antiviral defence upon a natural infection.