Optimal viral strategies for bypassing RNA silencing

The RNA silencing pathway constitutes a defence mechanism highly conserved in eukaryotes, especially in plants, where the underlying working principle relies on the repressive action triggered by the intracellular presence of double-stranded RNAs. This immune system performs a post-transcriptional suppression of aberrant mRNAs or viral RNAs by small interfering RNAs (siRNAs) that are directed towards their target in a sequence-specific manner. However, viruses have evolved strategies to escape from silencing surveillance while promoting their own replication. Several viruses encode suppressor proteins that interact with different elements of the RNA silencing pathway and block it. The different suppressors are not phylogenetically nor structurally related and also differ in their mechanism of action. Here, we adopt a model-driven forward-engineering approach to understand the evolution of suppressor proteins and, in particular, why viral suppressors preferentially target some components of the silencing pathway. We analysed three strategies characterized by different design principles: replication in the absence of a suppressor, suppressors targeting the first protein component of the pathway and suppressors targeting the siRNAs. Our results shed light on the question of whether a virus must opt for devoting more time into transcription or into translation and on which would be the optimal step of the silencing pathway to be targeted by suppressors. In addition, we discussed the evolutionary implications of such designing principles.