Our understanding of how rotavirus (RV) subverts host innate immune signaling has greatly increased over the past decade. However, the relative contribution of each virus-encoded innate immune antagonist has not been fully studied in the context of RV infection in vivo Here, we present both in vitro and in vivo evidence that the host interferon (IFN)-inducible 2'-5'-oligoadenylate synthetase (OAS) and RNase L pathway effectively suppresses the replication of heterologous RV strains. VP3 from homologous RVs relies on its 2'-5'-phosphodiesterase (PDE) domain to counteract RNase L-mediated antiviral signaling. Using an RV reverse-genetics system, we show that compared to the parental strain, VP3 PDE mutant RVs replicated at low levels in the small intestine and were shed less in the feces of wild-type mice, and such defects were rescued in Rnasel -/- suckling mice. Collectively, these findings highlight an important role of VP3 in promoting viral replication and pathogenesis in vivo in addition to its well-characterized function as the viral RNA-capping enzyme.IMPORTANCE Rotaviruses are significant human pathogens that result in diarrhea, dehydration, and deaths in many children around the world. Rotavirus vaccines have suboptimal efficacy in low- to middle-income countries, where the burden of the diseases is the most severe. With the ultimate goal of improving current vaccines, we aim to better understand how rotavirus interacts with the host innate immune system in the small intestine. Here, we demonstrate that interferon-activated RNase L signaling blocks rotavirus replication in a strain-specific manner. In addition, virus-encoded VP3 antagonizes RNase L activity both in vitro and in vivo These studies highlight an ever-evolving arms race between antiviral factors and viral pathogens and provide a new means of targeted attenuation for next-generation rotavirus vaccine design.

中文翻译：

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反向遗传学揭示了轮状病毒 VP3 磷酸二酯酶活性在抑制 RNase L 信号转导和促进肠道病毒体内复制方面的作用。

在过去十年中，我们对轮状病毒 (RV) 如何破坏宿主先天免疫信号的理解有了很大的提高。然而，在体内 RV 感染的背景下，每种病毒编码的先天免疫拮抗剂的相对贡献尚未得到充分研究在这里，我们提供体外和体内证据表明宿主干扰素 (IFN) 可诱导 2'-5 '-寡聚腺苷酸合成酶 (OAS) 和 RNase L 通路有效抑制异源 RV 菌株的复制。来自同源 RV 的 VP3 依赖于其 2'-5'-磷酸二酯酶 (PDE) 结构域来抵消 RNase L 介导的抗病毒信号传导。使用 RV 反向遗传学系统，我们表明，与亲代菌株相比，VP3 PDE 突变体 RV 在小肠中以低水平复制，并且在野生型小鼠的粪便中脱落较少，这种缺陷在 Rnasel -/- 乳鼠身上得以挽救。总的来说，这些发现突出了 VP3 在体内促进病毒复制和发病机制方面的重要作用，以及其作为病毒 RNA 加帽酶的明确功能。 重要性轮状病毒是导致腹泻、脱水和死亡的重要人类病原体世界各地的许多儿童。轮状病毒疫苗在疾病负担最严重的中低收入国家效果欠佳。我们的最终目标是改进现有疫苗，旨在更好地了解轮状病毒如何与小肠中的宿主先天免疫系统相互作用。在这里，我们证明了干扰素激活的 RNase L 信号以毒株特异性方式阻断轮状病毒复制。此外，