Mammalian antiviral RNAi is on the move

Abstract

Recent work reported the existence of a mammalian cell-autonomous antiviral defence based on RNA interference (RNAi), which relies on the accumulation of virus-derived small interfering RNAs (vsiRNAs) to guide the degradation of complementary viral RNAs. In a new study, Zhang et al (2022) find that, in infected mice, vsiRNAs can enter the bloodstream via their incorporation into extracellular vesicles (EVs) and confer sequence-specific antiviral activity to recipient cells, thus indicating that mammalian antiviral RNAi participates in both cell-autonomous and non-cell-autonomous host defence.

Figure 1. Cell‐autonomous and non‐cell‐autonomous antiviral RNAi responses in mammals

Cell‐autonomous antiviral RNAi (left) is initiated with the cleavage of viral dsRNA replication intermediates by Dicer into vsiRNAs. These are loaded into Ago2 to form RISC that cleaves complementary viral RNAs and thereby restricts viral replication. Concomitantly, some vsiRNAs within the infected cells are incorporated into EVs released from multivesicular bodies (MVBs). These vsiRNAs‐containing EVs initiate non‐cell‐autonomous antiviral RNAi (right) via their secretion and dissemination through the bloodstream and deliver their content to the cytosol of non‐infected recipient cells possibly via endocytosis or fusion with the plasma membrane. Recipient cells primed with EV‐associated vsiRNAs can quickly prevent virus infection via RISC‐mediated cleavage of incoming viral genomes.