RNA interference, an emerging component of antiviral immunity in mammals

Abstract

Antiviral RNA interference (RNAi) is an immune pathway that can, in certain conditions, protect mammalian cells against RNA viruses. It depends on the recognition and dicing of viral double-stranded RNA by a protein of the Dicer family, which leads to the production of viral small interfering RNAs (vsiRNAs) that sequence-specifically guide the degradation of cognate viral RNA. If the first line of defence against viruses relies on type-I and type-III interferons (IFN) in mammals, certain cell types such as stem cells, that are hyporesponsive for IFN, instead use antiviral RNAi via the expression of a specific antiviral Dicer. In certain conditions, antiviral RNAi can also contribute to the protection of differentiated cells. Indeed, abundant vsiRNAs are detected in infected cells and efficiently guide the degradation of viral RNA, especially in cells infected with viruses disabled for viral suppressors of RNAi (VSRs), which are virally encoded blockers of antiviral RNAi. The existence and importance of antiviral RNAi in differentiated cells has however been debated in the field, because data document mutual inhibition between IFN and antiviral RNAi. Recent developments include the engineering of a small molecule inhibitor of VSR to probe antiviral RNAi in vivo, as well as the detection of vsiRNAs inside extracellular vesicles in the serum of infected mice. It suggests that using more complex, in vivo models could allow to unravel the contribution of antiviral RNAi to immunity at the host level.

Interplay between RNA interference and transposable elements in mammals

“…As part of RISC, siRNAs guide the degradation of viral genomes by the endonuclease Ago. Note that, while miRNA-driven RNAi does not canonically function through mRNA cleavage, antiviral RNAi largely depends on the enzymatic activity of mammalian Ago2 ( 3 ). Mammals encode a single Dicer gene, which protein product, Dicer, generates miRNAs for transcription regulation.…”

“…Mammals encode a single Dicer gene, which protein product, Dicer, generates miRNAs for transcription regulation. If several studies document human Dicer’s poor ability to target dsRNA for cleavage, the protein has been involved in dsRNA-driven antiviral RNAi in specific conditions ( 3 , 14 , 15 ). An additional isoform, termed antiviral Dicer (aviD), is produced by alternative splicing of mRNAs from the Dicer gene.…”

“…Both PRRs’ stimulation results in the activation of innate immunity and production of interferons, potentially leading to autoimmunity. If pathways of interferon activation are functional in differentiated cells, they are severely compromised in stem cells, including ESCs, which could explain why TE re-expression does not translate into interferon-driven cytotoxicity in this context ( 3 , 64 ). During age macular degeneration, expression of Alus in cells of the retinal pigmented epithelium leads to NLRP3 inflammasome activation and MyD88-dependent apoptosis, ultimately resulting in patient blindness ( 27 , 65 ).…”

“…Present in plants, fungi and animals, it relies on the inhibition of messenger RNA translation via the production of micro-RNAs (miRNAs), a family of small RNAs. Irrespective of its function in regulating gene expression, RNAi also carries a role in antiviral immunity ( 2 , 3 ). The machinery of RNAi is indeed equipped to recognize exogenous viral RNA and target it for cleavage, thereby thwarting infection.…”

Nucleic acid‐based small molecules as targeted transcription therapeutics for immunoregulation

“…As a rapidly evolving field, the technologies capable of advancing as targeted transcription therapeutics include the conventional RNA interference (RNAi) 19 and antisense oligonucleotides (ASOs), 20 the recent CRISPR-based transcriptional activation (CRISPRa), 21 and the PIP-based small molecule transcriptional regulators (Table 1). 12,13 Among the various methods available, PIP modulators have several advantages, such as target specificity, good cell permeability and diffusibility, stability, moderate immunogenicity, and relatively low production cost.…”