Extracellular RNA in viral–host interactions: Thinking outside the cell

Small RNAs and their associated RNA interference (RNAi) pathways underpin diverse mechanisms of gene regulation and genome defense across all three kingdoms of life and are integral to virus–host interactions. In plants, fungi and many animals, an ancestral RNAi pathway exists as a host defense mechanism whereby viral double‐stranded RNA is processed to small RNAs that enable recognition and degradation of the virus. While this antiviral RNAi pathway is not generally thought to be present in mammals, other RNAi mechanisms can influence infection through both viral‐ and host‐derived small RNAs. Furthermore, a burgeoning body of data suggests that small RNAs in mammals can function in a non‐cell autonomous manner to play various roles in cell‐to‐cell communication and disease through their transport in extracellular vesicles. While vesicular small RNAs have not been proposed as an antiviral defense pathway per se, there is increasing evidence that the export of host‐ or viral‐derived RNAs from infected cells can influence various aspects of the infection process. This review discusses the current knowledge of extracellular RNA functions in viral infection and the technical challenges surrounding this field of research. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs. RNA in Disease and Development > RNA in Disease. Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action;