A zebrafish model of Ifih1-driven Aicardi–Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients
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 larg...
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Frontiers Media S.A.
2023-11-01
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| author | Beatriz Bernal-Bermúdez Beatriz Bernal-Bermúdez Beatriz Bernal-Bermúdez Alicia Martínez-López Alicia Martínez-López Francisco J. Martínez-Morcillo Francisco J. Martínez-Morcillo Francisco J. Martínez-Morcillo Sylwia D. Tyrkalska Sylwia D. Tyrkalska Sylwia D. Tyrkalska Teresa Martínez-Menchón Teresa Martínez-Menchón Teresa Martínez-Menchón Pablo Mesa-del-Castillo Pablo Mesa-del-Castillo Pablo Mesa-del-Castillo María L. Cayuela María L. Cayuela María L. Cayuela Victoriano Mulero Victoriano Mulero Victoriano Mulero Diana García-Moreno Diana García-Moreno |
| author_facet | Beatriz Bernal-Bermúdez Beatriz Bernal-Bermúdez Beatriz Bernal-Bermúdez Alicia Martínez-López Alicia Martínez-López Francisco J. Martínez-Morcillo Francisco J. Martínez-Morcillo Francisco J. Martínez-Morcillo Sylwia D. Tyrkalska Sylwia D. Tyrkalska Sylwia D. Tyrkalska Teresa Martínez-Menchón Teresa Martínez-Menchón Teresa Martínez-Menchón Pablo Mesa-del-Castillo Pablo Mesa-del-Castillo Pablo Mesa-del-Castillo María L. Cayuela María L. Cayuela María L. Cayuela Victoriano Mulero Victoriano Mulero Victoriano Mulero Diana García-Moreno Diana García-Moreno |
| author_sort | Beatriz Bernal-Bermúdez |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-92385e9bf41d445988f7b8b5009a06fb |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-92385e9bf41d445988f7b8b5009a06fb2025-01-03T13:51:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12947661294766A zebrafish model of Ifih1-driven Aicardi–Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patientsBeatriz Bernal-Bermúdez0Beatriz Bernal-Bermúdez1Beatriz Bernal-Bermúdez2Alicia Martínez-López3Alicia Martínez-López4Francisco J. Martínez-Morcillo5Francisco J. Martínez-Morcillo6Francisco J. Martínez-Morcillo7Sylwia D. Tyrkalska8Sylwia D. Tyrkalska9Sylwia D. Tyrkalska10Teresa Martínez-Menchón11Teresa Martínez-Menchón12Teresa Martínez-Menchón13Pablo Mesa-del-Castillo14Pablo Mesa-del-Castillo15Pablo Mesa-del-Castillo16María L. Cayuela17María L. Cayuela18María L. Cayuela19Victoriano Mulero20Victoriano Mulero21Victoriano Mulero22Diana García-Moreno23Diana García-Moreno24Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainDepartamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainDepartamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainHospital Clínico Universitario Virgen de la Arrixaca, Murcia, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainHospital Clínico Universitario Virgen de la Arrixaca, Murcia, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainHospital Clínico Universitario Virgen de la Arrixaca, Murcia, SpainDepartamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Murcia, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainInstituto Murciano de Investigación Biosanitaria (IMIB)-Pascual Parrilla, Murcia, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, SpainType 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1294766/fulltype I IFNIFIH1zebrafish avatarautoimmunitydrug screening |
| spellingShingle | Beatriz Bernal-Bermúdez Beatriz Bernal-Bermúdez Beatriz Bernal-Bermúdez Alicia Martínez-López Alicia Martínez-López Francisco J. Martínez-Morcillo Francisco J. Martínez-Morcillo Francisco J. Martínez-Morcillo Sylwia D. Tyrkalska Sylwia D. Tyrkalska Sylwia D. Tyrkalska Teresa Martínez-Menchón Teresa Martínez-Menchón Teresa Martínez-Menchón Pablo Mesa-del-Castillo Pablo Mesa-del-Castillo Pablo Mesa-del-Castillo María L. Cayuela María L. Cayuela María L. Cayuela Victoriano Mulero Victoriano Mulero Victoriano Mulero Diana García-Moreno Diana García-Moreno A zebrafish model of Ifih1-driven Aicardi–Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients Frontiers in Immunology type I IFN IFIH1 zebrafish avatar autoimmunity drug screening |
| title | A zebrafish model of Ifih1-driven Aicardi–Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients |
| title_full | A zebrafish model of Ifih1-driven Aicardi–Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients |
| title_fullStr | A zebrafish model of Ifih1-driven Aicardi–Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients |
| title_full_unstemmed | A zebrafish model of Ifih1-driven Aicardi–Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients |
| title_short | A zebrafish model of Ifih1-driven Aicardi–Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients |
| title_sort | zebrafish model of ifih1 driven aicardi goutieres syndrome reproduces the interferon signature and the exacerbated inflammation of patients |
| topic | type I IFN IFIH1 zebrafish avatar autoimmunity drug screening |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1294766/full |
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