Mammalian antiviral systems directed by small RNA

Author summaryViruses are all around us and are likely inside some of the reader's cells at this moment. Organisms are accommodated to this reality and encode various immune systems to limit virus replication. In mammals, the best studied immune systems are directed by proteins that specifically recognize viruses. These include diverse antibodies and T cell receptors, which recognize viral proteins, and pattern recognition receptors, some of which can recognize viral nucleic acids. In other organisms, including bacteria, immune systems directed by small RNAs are also well known; spacer-derived guide RNAs in CRISPR/Cas immune systems are one prominent example. The small RNAs directing these systems derive their specificity via complementary base pairing with their targets, which include both host and viral nucleic acids. Rather than having "traded in" these systems for more advanced protein-directed systems, increasing evidence supports the perspective that small RNA-directed immune systems remain active in mammalian antiviral immunity in some contexts. Here, we review what is known so far about the emerging roles of mammalian siRNAs, miRNAs, piRNAs, and tRNAs in directing immunity to viruses. 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.