Enhanced RNAi does not provide efficient innate antiviral immunity in micein vivo

Abstract

In RNA interference (RNAi), long double-stranded RNA (dsRNA) is cleaved by Dicer endonuclease into small RNA interfering RNAs (siRNAs), which guide degradation of complementary RNAs. While RNAi mediates antiviral innate immunity in plants and many invertebrates, vertebrates adopted sequence-independent response and their Dicer produces siRNAs inefficiently because it is adapted to process small hairpin microRNA precursors in the gene-regulating microRNA pathway. Mammalian RNAi is thus a rudimentary pathway of unclear significance. To investigate its antiviral potential, we modified mouse Dicer locus to express a truncated variant (DicerΔHEL1) known to stimulate RNAi. Next, we analyzed how DicerΔHEL1/wtmice respond to four RNA viruses: Coxsackievirus B3 (CVB3) and encephalomyocarditis virus (ECMV) fromPicornaviridae; tick-borne encephalitis virus (TBEV) fromFlaviviridae; and lymphocytic choriomeningitis virus (LCMV) fromArenaviridae. Increased Dicer activity in DicerΔHEL1/wtmice did not elicit any antiviral effect. supporting insignificant antiviral function of endogenous mammalian RNAiin vivo. However, we also report that sufficiently high expression of DicerΔHEL1suppressed LCMV in embryonic stem cells and in a transgenic mouse model. Altogether, mice with increased Dicer activity offer a new benchmark for identifying and studying viruses susceptible to mammalian RNAiin vivo.