Induction and suppression of antiviral RNA interference (RNAi) has been observed in mammals during infection with at least seven distinct RNA viruses, including some that are pathogenic in humans. However, while the cell-autonomous immune response mediated by antiviral RNAi is gradually being recognized, little is known about systemic antiviral RNAi in mammals. Furthermore, extracellular vesicles (EVs) also function in viral signal spreading and host immunity. Here, we show that upon antiviral RNAi activation, virus-derived small-interfering RNAs (vsiRNAs) from Nodamura virus (NoV), Sindbis virus (SINV), and Zika virus (ZIKV) enter the murine bloodstream via EVs for systemic circulation. vsiRNAs in the EVs are biologically active, since they confer RNA-RNA homology-dependent antiviral activity in both cultured cells and infant mice. Moreover, we demonstrate that vaccination with a live-attenuated virus, rendered deficient in RNAi suppression, induces production of stably maintained vsiRNAs and confers protective immunity against virus infection in mice. This suggests that vaccination with live-attenuated VSR (viral suppressor of RNAi)-deficient mutant viruses could be a new strategy to induce immunity.

中文翻译：

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小鼠循环细胞外囊泡含有抗病毒免疫活性的病毒衍生 siRNA。

在哺乳动物感染至少七种不同的 RNA 病毒（包括一些对人类具有致病性的病毒）期间，已经观察到抗病毒 RNA 干扰 (RNAi) 的诱导和抑制。然而，虽然抗病毒 RNAi 介导的细胞自主免疫反应逐渐被认识，但对哺乳动物的系统性抗病毒 RNAi 知之甚少。此外，细胞外囊泡 (EV) 还在病毒信号传播和宿主免疫中发挥作用。在这里，我们表明，在抗病毒 RNAi 激活后，来自野田村病毒 (NoV)、辛德毕斯病毒 (SINV) 和寨卡病毒 (ZIKV) 的病毒衍生小干扰 RNA (vsiRNA) 通过 EV 进入小鼠血液进行全身循环。EV 中的 vsiRNA 具有生物活性，因为它们在培养细胞和幼鼠中均具有 RNA-RNA 同源依赖性抗病毒活性。而且，我们证明，用减毒活病毒接种疫苗，导致 RNAi 抑制缺陷，诱导稳定维持的 vsiRNA 的产生，并赋予小鼠抗病毒感染的保护性免疫力。这表明使用减毒活 VSR（RNAi 病毒抑制因子）缺陷型突变病毒进行疫苗接种可能是诱导免疫的新策略。