The dynamics and efficacy of antiviral RNA silencing: A model study

Marian Ac Groenenboom,Paulien Hogeweg

doi:10.1186/1752-0509-2-28

Abstract

BackgroundMathematical modeling is important to provide insight in the complicated pathway of RNA silencing. RNA silencing is an RNA based mechanism that is widely used by eukaryotes to fight viruses, and to control gene expression.ResultsWe here present the first mathematical model that combines viral growth with RNA silencing. The model involves a plus-strand RNA virus that replicates through a double-strand RNA intermediate. The model of the RNA silencing pathway consists of cleavage of viral RNA into siRNA by Dicer, target cleavage of viral RNA via the RISC complex, and a secondary response. We found that, depending on the strength of the silencing response, different viral growth patterns can occur. Silencing can decrease viral growth, cause oscillations, or clear the virus completely. Our model can explain various observed phenomena, even when they seem contradictory at first: the diverse responses to the removal of RNA dependent RNA polymerase; different viral growth curves; and the great diversity in observed siRNA ratios.ConclusionThe model presented here is an important step in the understanding of the natural functioning of RNA silencing in viral infections.

Highlights

Mathematical modeling is important to provide insight in the complicated pathway of RNA silencing
The long stretches of double-strand RNA (dsRNA) that are formed during replication may not be accessible for Dicer [10], and recently it has been suggested that viral singlestrand RNA is cleaved into small interfering RNAs (siRNAs) [11]
We here model a replicating plusstrand RNA virus, and we extend our model of the silencing pathway with the kinetics of RISC, siRNA loaded RISC, Dicer and RNA dependent RNA polymerase (RDR), since we expect that the ability of the pathway to silence viruses will strongly depend on these proteins

Summary

Introduction

Mathematical modeling is important to provide insight in the complicated pathway of RNA silencing. The key mediators of RNA silencing are small RNAs [4,5], that are cleaved from stem loop RNA or long stretches of double-strand RNA (dsRNA) by the enzyme Dicer [6,7]. The general view is that in antiviral silencing small interfering RNAs (siRNAs) are cleaved from long stretches of dsRNA, that are produced by the virus as intermediates in replication. The double-stranded siRNA associates with the protein complex RISC. The siRNA strand with the 5' lowest stability is selected to guide the RISC complex to the target. The long stretches of dsRNA that are formed during replication may not be accessible for Dicer [10], and recently it has been suggested that viral singlestrand RNA (ssRNA) is cleaved into siRNAs [11]

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