PDF(Pubmed)
Abstract：
Type I interferonopathies are a heterogenic group of rare diseases associated with an increase in type I interferon (IFN). The main challenge for the study of Type I interferonopathies is the lack of a well-founded animal model to better characterize the phenotype as well as to perform fast and large drug screenings to offer the best treatment options. In this study, we report the development of a transgenic zebrafish model of Type I interferonopathy overexpressing ifih1 carrying the mutation p.Arg742His (Tg(ifih1_mut)), corresponding to the human mutation p.Arg779His. RNA sequence analysis from Tg(ifih1_mut) larvae revealed a systemic inflammation and IFN signature upon a suboptimal poly I:C induction compared with wild-type larvae, confirming the phenotype observed in patients suffering from Type I interferonopathies. More interestingly, the phenotype was manifested in the zebrafish inflammation and Type I IFN reporters nfkb:eGFP and isg15:eGFP, respectively, making this zebrafish model suitable for future high-throughput chemical screening (HTS). Using the unique advantages of the zebrafish model for gene editing, we have generated Tg(ifih1_mut) knocked down for mavs and ikbke, which completely abrogated the Poly I:C induction and activation of the GFP of the reporters. Finally, we used an FDA-approved drug, Baricitinib (Jak1/Jak2 inhibitor), which was able to reduce the inflammation and the ISG expression. Our results demonstrate the potential of this model to further understand AGS pathological mechanisms and to identify novel therapeutic drugs by HTS.
摘要：
I型干扰素病是与I型干扰素（IFN）增加相关的罕见疾病的异源性组。研究I型干扰素病的主要挑战是缺乏建立良好的动物模型来更好地表征表型以及进行快速和大的药物筛选以提供最佳治疗选择。在这项研究中,我们报道了过表达ifih1的I型干扰素病的转基因斑马鱼模型的发展，该模型携带突变p.Arg742His（Tg（ifih1_mut）），对应于人类突变p.Arg779His。与野生型幼虫相比，Tg（ifih1_mut）幼虫的RNA序列分析揭示了系统性炎症和IFN特征，证实在患有I型干扰素病的患者中观察到的表型。更有趣的是，表型表现在斑马鱼炎症和I型IFN报道者nfkb：eGFP和isg15：eGFP，分别,使这种斑马鱼模型适用于未来的高通量化学筛选（HTS）。利用斑马鱼模型的独特优势进行基因编辑,我们已经产生了Tg（ifih1_mut）击倒小牛和ikbke，这完全取消了PolyI:C诱导和报道分子的GFP激活。最后,我们用了FDA批准的药物,Baricitinib（Jak1/Jak2抑制剂），能够减少炎症和ISG表达。我们的结果表明该模型具有进一步了解AGS病理机制和通过HTS鉴定新型治疗药物的潜力。
