Mammalian antiviral systems directed by small RNA

Abstract

There are strong incentives for human populations to develop antiviral systems. Similarly, genomes that encode antiviral systems have had strong selective advantages. Protein-guided immune systems, which have been well studied in mammals, are necessary for survival in our virus-laden environments. Small RNA-directed antiviral immune systems suppress invasion of cells by non-self genetic material via complementary base pairing with target sequences. These RNA silencing-dependent systems operate in diverse organisms. In mammals, there is strong evidence that microRNAs (miRNAs) regulate endogenous genes important for antiviral immunity, and emerging evidence that virus-derived nucleic acids can be directly targeted by small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNAs (tRNAs) for protection in some contexts. In this review, we summarize current knowledge of the antiviral functions of each of these small RNA types and consider their conceptual and mechanistic overlap with innate and adaptive protein-guided immunity, including mammalian antiviral cytokines, as well as the prokaryotic RNA-guided immune system, CRISPR. In light of recent successes in delivery of RNA for antiviral purposes, most notably for vaccination, we discuss the potential for development of small noncoding RNA-directed antiviral therapeutics and prophylactics.

Fig 1. Overview of antiviral siRNA/miRNA pathways and inhibitory factors.

Endogenous miRNAs are transcribed from the genome as pri-miRNAs and are processed into pre-miRNAs by the Drosha/DGCR8 complex. Pre-miRNAs are exported to the cytoplasm and are processed into miRNA duplexes by Dicer and its partner protein complex. Viral RNAs are capable of being processed by the same ribonucleases; however, some VSRs or ISGs are reported to inhibit the processing of small RNAs in mammalian cells. Mature miRNAs or siRNAs silence both endogenous and exogenous RNAs loaded on AGO proteins in collaboration with various RNA silencing regulators for the antiviral functions. Endogenous nucleic acids and proteins: blue; viral nucleic acids and proteins: red. AGO, argonaute; dsRNA, double-stranded RNA; ISG, IFN-stimulated gene; miRNA, microRNA; pre-miRNA, precursor miRNA; pri-miRNA, primary transcript; siRNA, small interfering RNA; VSR, viral suppressor of RNAi.

Fig 2. Overview of antiviral piRNA pathway and antiviral tRFs.

piRNAs with antiviral potential can be generated via several mechanisms: primary processing of piRNA cluster transcripts that contain an EVE, direct non-piRNA guided cleavage of viral RNA via a Piwi protein (vpiRNA), EVE-derived piRNA- or vpiRNA-guided cleavage of viral RNAs via a ping-pong amplification loop, or PIWI interactions with virus-homologous noncanonical piRNAs such as tRFs. EVE, endogenous viral element; piRNA, PIWI-interacting RNA; tRF, tRNA fragment; vpiRNA, virus-specific PIWI-interacting RNA.