A zebrafish model of Ifih1-driven Aicardi-Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients

Front Immunol. 2023 Nov 24:14:1294766. doi: 10.3389/fimmu.2023.1294766. eCollection 2023.

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.

Keywords: IFIH1; autoimmunity; drug screening; type I IFN; zebrafish avatar.

Publication types

  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Animals
  • Humans
  • Inflammation / genetics
  • Interferon Type I* / genetics
  • Interferon-Induced Helicase, IFIH1
  • Poly I
  • Zebrafish* / genetics

Substances

  • Interferon Type I
  • Poly I
  • Interferon-Induced Helicase, IFIH1

Supplementary concepts

  • Aicardi-Goutieres syndrome

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project "CP21/00028" and research grant PI22/0089 and co-funded by the European Union to DG-M) and Consejería de Salud de la Región de Murcia (ZEBER project to MC and VM), Spanish Ministry of Science and Innovation (Juan de la Cierva-Incorporacion postdoctoral contract to ST). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.