An isoform of Dicer protects mammalian stem cells against multiple RNA viruses

In mammals, early resistance to viruses relies on interferons, which protect differentiated but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialised Dicer protein that cleaves viral double stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. Here we identify an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses, including Zika virus and SARS-CoV-2, by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity in which different cell-intrinsic antiviral pathways are tailored to the differentiation status of cells. Overall design: Mouse brain organoids were infected with ZIKV or SARS-CoV-2 for 4 days. RNA was extracted from infected organoids and deep-sequenced.