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RNA-based antiviral immunity

Key Points

  • RNA-based antiviral immunity is active in diverse host species, which produce virus-derived small RNAs in infected cells and use them as specificity determinants to guide specific virus clearance.

  • Specific members of the Dicer family of proteins, which encode RNA helicase, double-stranded RNA (dsRNA)-binding and dsRNA-specific RNase domains, function as pattern recognition receptors (PRRs) in fungi, plants and invertebrates to detect viral dsRNA as a pathogen-associated molecular pattern (PAMP) and to further process it into virus-derived small interfering RNAs (siRNAs).

  • Viral siRNAs are structurally similar to host endogenous siRNAs with monophosphate groups at the 5′ end and 2′-O-methyl groups at the 3′ end. They guide specific clearance of the invading viral RNAs by members of the Argonaute (AGO) protein family.

  • Amplification of viral siRNAs by a host RNA-dependent RNA polymerase (RdRP) has an essential role in RNA-based antiviral immunity in plants. Distinct families of cellular RdRPs are conserved in all eukaryotes.

  • Recent deep sequencing has identified siRNA-like virus-derived small RNAs in mammalian cells infected with distinct RNA viruses. However, it is not clear whether these viral small RNAs function in RNA-based viral immunity or other aspects of viral immunity and pathogenesis.

  • Many nucleus-replicating DNA viruses that infect vertebrates and invertebrates encode up to 25 microRNAs (miRNAs) to regulate the expression of viral and host genes implicated in viral immunity and pathogenesis.

  • The recent discovery of virus-derived Piwi-interacting RNAs (piRNAs) in infected Drosophila melanogaster cells, which are larger than the 21-nucleotide viral siRNAs, suggests that piRNAs might have a novel antiviral function in addition to their role in genome defence against transposons and repeat elements.

Abstract

In eukaryotic RNA-based antiviral immunity, viral double-stranded RNA is recognized as a pathogen-associated molecular pattern and processed into small interfering RNAs (siRNAs) by the host ribonuclease Dicer. After amplification by host RNA-dependent RNA polymerases in some cases, these virus-derived siRNAs guide specific antiviral immunity through RNA interference and related RNA silencing effector mechanisms. Here, I review recent studies on the features of viral siRNAs and other virus-derived small RNAs from virus-infected fungi, plants, insects, nematodes and vertebrates and discuss the innate and adaptive properties of RNA-based antiviral immunity.

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Figure 1: Drosophila melanogaster encodes three small RNA pathways that are highly conserved in mammals.
Figure 2: Key steps in RNA-based antiviral immunity induced in Drosophila melanogaster by infection of positive-strand RNA viruses such as flock house virus.
Figure 3: The replication cycle of a positive-strand RNA virus includes multiple steps that yield double- stranded RNA.
Figure 4: Plant small RNA pathways.
Figure 5: A model for RNA-based antiviral immunity induced in Arabidopsis thaliana by infection of positive-strand RNA viruses such as cucumber mosaic virus.

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Acknowledgements

Work in my laboratory is supported by grants from the US National Institutes of Health, the United States Department of Agriculture, California Citrus Research Board and UC Discovery. Because of space limitations I have often cited reviews rather than primary research papers. I apologize to those investigators whose original papers have not been cited.

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Glossary

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in pathogens but not mammalian cells. Examples include various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind to Toll-like receptors.

Pattern recognition receptors

(PRRs). Host receptors (such as Toll-like receptors (TLRs), NOD-like receptors (NLRs) or RIG-I-like receptors (RLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (such as TLRs) or soluble cytoplasmic receptors (such as RIG-I, melanoma differentiation-associated gene 5 (MDA5) and NLRs).

Small interfering RNAs

(siRNAs). 21–24-nucleotide double-stranded RNAs with two-nucleotide 3′ overhangs and 5′-monophosphate and 3′-hydroxyl termini. They are processed from long double-stranded RNA precursors by Dicer. Plant and animal genomes encode many siRNAs with complete or extensive sequence complementarity to endogenous mRNA transcripts.

MicroRNAs

(miRNAs). 21–25-nucleotide single-stranded RNAs with 5′-monophosphate and 3′-hydroxyl termini. They are processed by Dicer from a structured region of single-stranded nuclear transcripts. The seed region of miRNAs corresponds to nucleotides 2–8 and seed pairing has a crucial role in the recognition of the target mRNA.

Piwi-interacting RNAs

(piRNAs). 24–31-nucleotide single-stranded RNAs with 5′-monophosphate and 3′-hydroxyl termini. They are independent of Dicer for biogenesis, bind to the Piwi subfamily of Argonaute (AGO) proteins for function and are found in animals but not in plants, possibly because plants do not encode any AGO protein in the Piwi subfamily.

RNA interference

(RNAi). Specific gene silencing that is induced by long double-stranded RNA or small interfering RNAs. It is used widely to knock down gene expression in plants and animals.

RNA silencing

Specific gene silencing guided by all classes of small silencing RNAs such as siRNAs, miRNAs and piRNAs.

Piwi domain

The highly conserved carboxy-terminal domain of Argonaute (AGO) proteins, which contains an RNase H motif. The catalytic centre consists of a DDH triad that functions as a metal coordinating site. AGO binding to a target RNA that is highly complementary to the loaded small interfering RNA brings the scissile phosphate, opposite nucleotides 10 and 11 of the small RNA guide, into the enzyme active site, allowing cleavage of the target RNA to leave 5′-monophosphate and 3′-hydroxyl termini.

RNA-induced silencing complex

(RISC). The effector complex of RNA silencing that contains at least two components: a single-stranded small interfering RNA or microRNA and an AGO protein.

Positive-strand RNA virus

((+)RNA virus). These viruses use RNA as genetic material. Their virions contain single-stranded genomic RNA that functions directly as mRNA and is sufficient to initiate viral infection after entry into a host cell. Tobacco mosaic virus, poliovirus and hepatitis C virus are examples.

Subgenomic RNA

RNA transcripts of the viral RNA genome that contain only part of the sequence present in the entire genome and usually function as mRNA.

Deep sequencing

Also referred to as next-generation sequencing. This includes the Roche 454, Illumina and other high-throughput DNA sequencing platforms.

dsRNA uptake pathway

The endocytic pathway that mediates cell entry of double-stranded RNA in insect cells.

Systemic silencing

RNA silencing that occurs in tissues distant from the site where RNA silencing is initially induced, as a result of non-cell autonomous spread of RNA silencing in plants and Caenorhabditis elegans.

Secondary siRNAs

Small interfering RNAs (siRNAs) produced by processes that require a cellular RNA-dependent RNA polymerase, in contrast to primary siRNAs that are diced from exogenous double-stranded RNA (dsRNA) or dsRNA synthesized by viral RNA-dependent RNA polymerase.

Satellite RNA

Non-coding linear or circular RNA molecules of a few hundred nucleotides in length that are replicated and packaged into virions by a 'helper virus', but have no significant sequence homology with the 'helper virus' genome. Different strains of satellite RNA may attenuate or intensify the disease symptoms induced by the helper virus.

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Ding, SW. RNA-based antiviral immunity. Nat Rev Immunol 10, 632–644 (2010). https://doi.org/10.1038/nri2824

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