The activation of antiviral RNA interference not only exists in neural progenitor cells but also in somatic cells in mammals

Abstract

The RNA interference (RNAi) pathway directs an important antiviral immunity mechanism in plants and invertebrates. Recently, we and others have demonstrated that the antiviral RNAi response is also conserved in mammals, at least to five distinct RNA viruses, including Zika virus (ZIKV). ZIKV may preferentially infect neuronal progenitor cells (NPCs) in the developing foetal brain. Ex vivo ZIKV infection induces RNAi-mediated antiviral response in human NPCs, but not in the more differentiated NPCs or somatic cells. However, litter is known about the in vivo property or function of the virus-derived small-interfering RNAs (vsiRNAs) targeting ZIKV. Here we report a surprising observation: different from ex vivo observations, viral small RNAs (vsRNAs) targeting ZIKV were produced in vivo upon infection in both central neuron system (CNS) and muscle tissues. In addition, our findings demonstrate the production of canonical vsiRNAs in murine CNS upon antiviral RNAi activation by Sindbis virus (SINV), suggesting the possibility of antiviral immune strategy applied by mammals in the CNS.

Efficient Dicer processing of virus-derived double-stranded RNAs and its modulation by RIG-I-like receptor LGP2

“…Recent studies have provided evidence for the induction of the antiviral RNAi response in mammals [20][21][22][23][24][25][26][27][28]. These studies, including ours, have demonstrated production of abundant vsiRNAs predominantly 22 nucleotides (nt) long during the infection of undifferentiated and differentiated cells as well as mice with positive-or negative-strand RNA viruses [23][24][25][26][27][28][29][30].…”

“…We further determined whether the B2 protein of NoV acts as a functional VSR when expressed from a heterologous positive-strand RNA virus, Sindbis virus (SINV), recently documented to trigger production of vsiRNAs in infected brain tissues of suckling mice after intracranial inoculation [28]. We first cloned and sequenced the total small RNAs from hind limb muscle tissue of BALB/c suckling mice inoculated by intraperitoneal injection.…”

“…and development [28,62]. In this work, we investigated whether production of SINV-targeting vsiRNAs in mice prior to SINV inoculation could enhance the inhibition of SINV infection.…”

“…Recent studies have provided evidence for the induction of the antiviral RNAi response in mammals [20][21][22][23][24][25][26][27][28]. These studies, including ours, have demonstrated production of abundant vsiRNAs predominantly 22 nucleotides (nt) long during the infection of undifferentiated and differentiated cells as well as mice with positive-or negative-strand RNA viruses [23][24][25][26][27][28][29][30]. Notably, Nodamura virus (NoV), influenza A virus (IAV), human enterovirus 71 (HEV71), and dengue virus-2 (DNV2) from 4 distinct RNA virus families encode structurally unrelated VSRs necessary for infection and active to suppress Dicer processing of the cognate viral dsRNA replicative intermediates (dsRNA-vRIs) into vsiRNAs [23][24][25]27,29].…”

Zebrafish as an animal model for the antiviral RNA interference pathway

“…SINV, a prototypic alphavirus of the family Togaviridae possessing a non-segmented single-strand positive-sense RNA genome, and VSV, a single-strand negative-sense RNA virus from the family Rhabdoviridae, have been widely employed to investigate infection and immunity, including antiviral RNAi, in various model organisms, such as D. melanogaster [6,29,30], C. elegans [31,32] and mice [14]. Preliminary studies have suggested that both SINV and VSV can establish robust infection in zebrafish [25,26].…”