2. Academic Validation
  3. Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency

Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency

  • J Allergy Clin Immunol. 2021 Aug;148(2):381-393. doi: 10.1016/j.jaci.2021.03.045.
Stefano Vavassori 1,  Janet Chou 2,  Laura Eva Faletti 3,  Veronika Haunerdinger 4,  Lennart Opitz 5,  Pascal Joset 6,  Christopher J Fraser 7,  Seraina Prader 1,  Xianfei Gao 8,  Luise A Schuch 8,  Matias Wagner 9,  Julia Hoefele 9,  Maria Elena Maccari 3,  Ying Zhu 10,  George Elakis 10,  Michael T Gabbett 11,  Maria Forstner 8,  Heymut Omran 12,  Thomas Kaiser 12,  Christina Kessler 12,  Heike Olbrich 12,  Patrick Frosk 13,  Abduarahman Almutairi 14,  Craig D Platt 2,  Megan Elkins 2,  Sabrina Weeks 2,  Tamar Rubin 15,  Raquel Planas 1,  Tommaso Marchetti 1,  Danil Koovely 1,  Verena Klämbt 16,  Neveen A Soliman 17,  Sandra von Hardenberg 18,  Christian Klemann 19,  Ulrich Baumann 19,  Dominic Lenz 20,  Andreas Klein-Franke 21,  Martin Schwemmle 22,  Michael Huber 23,  Ekkehard Sturm 24,  Steffen Hartleif 24,  Karsten Häffner 25,  Charlotte Gimpel 25,  Barbara Brotschi 26,  Guido Laube 27,  Tayfun Güngör 4,  Michael F Buckley 10,  Raimund Kottke 28,  Christian Staufner 20,  Friedhelm Hildebrandt 16,  Simone Reu-Hofer 29,  Solange Moll 30,  Achim Weber 31,  Hundeep Kaur 32,  Stephan Ehl 3,  Sebastian Hiller 32,  Raif Geha 33,  Tony Roscioli 34,  Matthias Griese 8,  Jana Pachlopnik Schmid 35
Affiliations

Affiliations

  • 1 Division of Immunology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
  • 2 Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
  • 3 Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 4 Division of Stem Cell Transplantation and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
  • 5 Functional Genomics Center Zürich, University of Zurich, Zurich, Switzerland.
  • 6 Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
  • 7 Queensland Children's Hospital, South Brisbane, Australia.
  • 8 Division of Pediatric Pneumology, Dr. von Hauner Children's Hospital, University Hospital Munich, German Center for Lung Research (DZL), Munich, Germany.
  • 9 Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
  • 10 New South Wales Health Pathology Genomics, Prince of Wales Hospital, Sydney, Australia.
  • 11 Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.
  • 12 Clinic for General Pediatrics, University Hospital Münster, Münster, Germany.
  • 13 Division of Clinical Immunology and Allergy, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada.
  • 14 Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
  • 15 Division of Pediatric Clinical Immunology and Allergy, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada.
  • 16 Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
  • 17 Department of Pediatrics, Center of Pediatric Nephrology and Transplantation, Cairo University, Cairo, Egypt.
  • 18 Department of Human Genetics, Hannover Medical School, Hannover, Germany.
  • 19 Department of Paediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
  • 20 Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  • 21 Division of Pediatric Hematology and Oncology, Cantonal Hospital Aarau, Aarau, Switzerland.
  • 22 Institute of Virology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 23 Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
  • 24 Division of Pediatric Gastroenterology and Hepatology, University Hospital Tübingen, Tübingen, Germany.
  • 25 Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 26 Department of Pediatric and Neonatal Intensive Care, University Children's Hospital Zurich, Zurich, Switzerland.
  • 27 Division of Nephrology, University Children's Hospital Zurich, Zurich, Switzerland.
  • 28 Division of Neuroradiology, Department of Diagnostic Imaging and Intervention, University Children's Hospital Zurich, Zurich, Switzerland.
  • 29 Institute of Pathology, University of Würzburg, Würzburg, Germany.
  • 30 Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
  • 31 Department of Pathology and Molecular Pathology, and Institute of Molecular Cancer Research, University Hospital and University of Zurich, Zurich, Switzerland.
  • 32 Biozentrum, University of Basel, Basel, Switzerland.
  • 33 Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass. Electronic address: [email protected].
  • 34 New South Wales Health Pathology Genomics, Prince of Wales Hospital, Sydney, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Sydney, Australia; Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; Neuroscience Research Australia, University of New South Wales, Sydney, Australia.
  • 35 Division of Immunology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; Pediatric Immunology, University of Zurich, Zurich, Switzerland. Electronic address: [email protected].
PMID: 33872655 DOI: 10.1016/j.jaci.2021.03.045
Abstract

Background: Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated Antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known.

Objective: We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease.

Methods: Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids.

Results: Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes.

Conclusion: ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.

Keywords

HLH-like disease; ZNFX1; brain calcification; interstitial lung disease; leukoencephalopathy; susceptibility to viral infections; thrombotic microangiopathy; type I interferon; virally induced hepatitis.

Figures