Abstract
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 RNAsRNA in Disease and Development > RNA in DiseaseRegulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action
Highlights
Another study showed that human immunodeficiency virus (HIV)-encoded miRNAs derived from the viral long terminal repeat region, vmiR88 and vmiR99 are transferred in extracellular vesicles (EVs) and stimulate TNFα release from recipient macrophages through TLR8 signaling (Barclay et al, 2017; Bernard et al, 2014; Sampey et al, 2016)
This study found hepatitis B surface proteins (HBs)-associated miRNAs to be different from EV-miRNAs released from infected cells, which could indicate distinct mechanisms of miRNA sorting and secretion (Novellino et al, 2012)
Sequencing analyses of the RNA found in different body fluids have dominated this field, with less focus on how the RNA became extracellular and whether it is directed to a specific target
Summary
We cover the properties and functions of extracellular small RNAs that have been reported in a viral context, starting with a focus on miRNAs and how their transfer in EVs to recipient cells might impact infection through canonical (gene silencing) or noncanonical (Toll-like receptor [TLR] activation) mechanisms. A subsequent study by the same group showed that other classes of viral small RNAs from EBV-infected cells are exported and can be transferred to recipient cells where they can activate immune responses.
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