Lork Marie, Childs Liam, Lieber Gauthier, Kwaschik Florence, König Renate, Hale Benjamin G
Institute of Medical Virology, University of Zurich, Zurich, 8057, Switzerland.
Host-Pathogen Interactions, Paul-Ehrlich-Institut, Langen, 63225, Germany.
EMBO Rep. 2025 Jun 16. doi: 10.1038/s44319-025-00498-2.
Influenza A virus (IAV) infection triggers derepression of host transposable elements (TEs), which have the potential to form double-stranded (ds)RNAs and could enhance innate antiviral immunity. However, the contribution of TEs to stimulating such pathways during infection is unknown, and it remains unclear whether derepressed TEs actually form dsRNAs. Here, we perform strand-specific total RNA-Seq on nucleus-associated and cytosolic fractions from cells infected with wild-type IAV or an engineered IAV lacking NS1, a dsRNA-binding interferon-antagonist protein. Both infections globally increase levels of host TE RNAs with bioinformatic and experimental evidence for double-strandedness. However, NS1-deficient IAV leads to significantly more of these putative dsRNA-forming TEs accumulating in the cytosolic fraction. Co-precipitations identify that wild-type NS1, but not a dsRNA-binding mutant, associates with these TEs, and microscopy shows co-localization of wild-type NS1 with dsRNA in perinuclear regions. Our data reveal the double-stranded nature of some IAV-triggered host TEs and suggest that NS1-mediated sequestration could limit their engagement of cytosolic innate immune sensors.
甲型流感病毒（IAV）感染会引发宿主转座元件（TEs）的去抑制，这些转座元件有可能形成双链（ds）RNA，并可能增强先天性抗病毒免疫力。然而，TEs在感染过程中对刺激此类途径的作用尚不清楚，而且去抑制的TEs是否真的形成dsRNA也仍不明确。在这里，我们对感染野生型IAV或缺乏NS1（一种dsRNA结合干扰素拮抗剂蛋白）的工程化IAV的细胞的核相关和胞质部分进行链特异性总RNA测序。两种感染都会使宿主TE RNA的水平整体升高，并有生物信息学和双链性的实验证据。然而，缺乏NS1的IAV会导致更多这些假定的形成dsRNA的TEs在胞质部分积累。共沉淀实验表明野生型NS1而非dsRNA结合突变体与这些TEs相关联，显微镜观察显示野生型NS1与dsRNA在核周区域共定位。我们的数据揭示了一些IAV触发的宿主TEs的双链性质，并表明NS1介导的隔离可能会限制它们与胞质先天性免疫传感器的相互作用。
