Viruses represent a major threat for all animals, which defend themselves through induction of a large set of virus-stimulated genes that collectively control the infection. In vertebrates, these genes include interferons that play a critical role in the amplification of the response to infection. Virus- and interferon-stimulated genes include restriction factors targeting the different steps of the viral replication cycle, in addition to molecules associated with inflammation and adaptive immunity. Predictably, antiviral genes evolve dynamically in response to viral pressure. As a result, each animal has a unique arsenal of antiviral genes. Here, we exploit the capacity to experimentally activate the evolutionarily conserved STING signaling pathway by injection of the cyclic dinucleotide 2′3′-cGAMP into flies to define the repertoire of STING-regulated genes in ten Drosophila species, spanning 50 million years of evolution. Our data reveal a set of conserved STING-regulated factors, including STING itself, a cGAS-like receptor, the restriction factor pastrel, and the antiviral protein Vago, but also two key components of the antiviral RNA interference pathway, Dicer-2 and Argonaute2. In addition, we identify unknown species- or lineage-specific genes that have not been previously associated with resistance to viruses. Our data provide insight on the core antiviral response in Drosophila flies and pave the way for the characterization of previously unknown antiviral effectors.

中文翻译：

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通过 2'3'-cGAMP 反应的多物种比较研究果蝇 STING 依赖性抗病毒先天免疫的进化

病毒对所有动物来说都是一个主要威胁，它们通过诱导大量病毒刺激的基因来保护自己，这些基因共同控制感染。在脊椎动物中，这些基因包括干扰素，在增强感染反应方面发挥着关键作用。除了与炎症和适应性免疫相关的分子之外，病毒和干扰素刺激的基因还包括针对病毒复制周期不同步骤的限制因子。可以预见的是，抗病毒基因会根据病毒压力动态进化。因此，每种动物都有独特的抗病毒基因库。在这里，我们通过将环状二核苷酸 2'3'-cGAMP 注射到果蝇体内，利用实验激活进化上保守的 STING 信号通路的能力，定义了 10 个果蝇物种中 STING 调节基因的库，跨越了 5000 万年的进化。我们的数据揭示了一组保守的 STING 调节因子，包括 STING 本身、cGAS 样受体、限制因子 patrel 和抗病毒蛋白 Vago，还有抗病毒 RNA 干扰途径的两个关键成分 Dicer-2 和 Argonaute2 。此外，我们还鉴定了先前未与病毒抗性相关的未知物种或谱系特异性基因。我们的数据提供了对果蝇核心抗病毒反应的深入了解，并为以前未知的抗病毒效应物的表征铺平了道路。