Human Virus-Derived Small RNAs Can Confer Antiviral Immunity in Mammals

Abstract

RNA interference (RNAi) functions as a potent antiviral immunity in plants and invertebrates; however, whether RNAi plays antiviral roles in mammals remains unclear. Here, using human enterovirus 71 (HEV71) as a model, we showed HEV71 3A protein as an authentic viral suppressor of RNAi during viral infection. When the 3A-mediated RNAi suppression was impaired, the mutant HEV71 readily triggered the production of abundant HEV71-derived small RNAs with canonical siRNA properties in cells and mice. These virus-derived siRNAs were produced from viral dsRNA replicative intermediates in a Dicer-dependent manner and loaded into AGO, and they were fully active in degrading cognate viral RNAs. Recombinant HEV71 deficient in 3A-mediated RNAi suppression was significantly restricted in human somatic cells and mice, whereas Dicer deficiency rescued HEV71 infection independently of type I interferon response. Thus, RNAi can function as an antiviral immunity, which is induced and suppressed by a human virus, in mammals.

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

“…Further experimentation is therefore needed to address whether LGP2 acts in concert with other ISGs to suppress mammalian RNAi. The recent discovery that human enterovirus 71 encodes a VSR that interferes with Dicer activity to evade RNAi‐dependent restriction mechanisms (Qiu et al , 2017) opens up future avenues of research to assess the impact of LGP2 on mammalian antiviral RNAi.…”

“…However, Dicer's catalytic function appears mainly confined to precursor microRNA (pre‐miRNA) processing, and its antiviral capacity in mammals remains much debated (Parameswaran et al , 2010; Cullen et al , 2013; Li et al , 2013, 2016; Maillard et al , 2013; Backes et al , 2014; Ding & Voinnet, 2014; Kennedy et al , 2015; Jeffrey et al , 2017; tenOever, 2017). Some studies have reported that RNAi can impact antiviral immunity in mammals during influenza A virus, hepatitis C virus, Nodamura virus and, more recently, human enterovirus 71 infection (Wang et al , 2006; Matskevich & Moelling, 2007; Li et al , 2013, 2016; Maillard et al , 2013; Qiu et al , 2017). In contrast, others have found low abundance of viRNAs in mammalian somatic cells infected with various viruses, and only a modest effect of Dicer deficiency on viral replication, suggesting that RNAi is not an active mechanism of antiviral defence in most mammalian cell types (Parameswaran et al , 2010; Girardi et al , 2013; Backes et al , 2014; Bogerd et al , 2014; Schuster et al , 2017).…”

Noncanonical functions of microRNA pathway enzymes – Drosha, DGCR8, Dicer and Ago proteins

“…Mammalian Dicer also takes part in antiviral immunity via a mechanism in which Dicer processes viral dsRNA precursors into siRNAs that suppresses viral activity. These viral-derived siRNAs were not detected until recently because the viruses have evolved strategies to counteract such antiviral immunity by suppressing RNAi [58][59][60][61].…”

Main constraints for RNAi induced by expressed long dsRNA in mouse cells

“…In contrast to invertebrates, data supporting direct involvement of mammalian RNAi in antiviral defense are rather inconclusive. While a few studies suggested that RNAi could provide an effective antiviral response in ESCs and in mouse embryos Maillard et al, 2013;Qiu et al, 2017) other studies did not support that notion. For example, no siRNAs of viral origin have been found in human cells infected with a wide range of viruses (Pfeffer et al, 2005) or present siRNAs were not sufficient to mediate effective RNAi (Tsai et al, 2018).…”