Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency
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 dysb...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 30, 2021
|
| In: |
The journal of allergy and clinical immunology
Year: 2021, Volume: 148, Issue: 2, Pages: 381-393 |
| ISSN: | 1097-6825 |
| DOI: | 10.1016/j.jaci.2021.03.045 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.jaci.2021.03.045 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0091674921006138 
|
| Author Notes: | Stefano Vavassori, PhD, Janet Chou, MD, Laura Eva Faletti, PhD, Veronika Haunerdinger, PhD,Lennart Opitz, MS, Pascal Joset, PhD, Christopher J. Fraser, MD, Seraina Prader, MD, Xianfei Gao, MD, Luise A. Schuch, MS, Matias Wagner, MD, Julia Hoefele, MD, Maria Elena Maccari, MD, Ying Zhu, PhD, George Elakis, BSc, Michael T. Gabbett, MD, Maria Forstner, MD, Heymut Omran, MD, Thomas Kaiser, MD, Christina Kessler, MD, Heike Olbrich, PhD, Patrick Frosk, MD, PhD, Abduarahman Almutairi, MD, Craig D. Platt, MD, PhD, Megan Elkins, MSc, Sabrina Weeks, BA, Tamar Rubin, MD, Raquel Planas, PhD, Tommaso Marchetti, MS, Danil Koovely, MS, Verena Kl€ambt, MD, Neveen A. Soliman, MD, PhD, Sandra von Hardenberg, PhD, Christian Klemann, MD, Ulrich Baumann, MD, Dominic Lenz, MD, Andreas Klein-Franke, MD, Martin Schwemmle, PhD, Michael Huber, PhD, Ekkehard Sturm, MD, PhD, Steffen Hartleif, MD, Karsten H€affner, MD, Charlotte Gimpel, MB, BChir, MA, Barbara Brotschi, MD, Guido Laube, MD, Tayfun Güngör, MD, Michael F. Buckley, MD, Raimund Kottke, MD, Christian Staufner, MD, Friedhelm Hildebrandt, MD, Simone Reu-Hofer, MD, Solange Moll, MD, Achim Weber, MD, Hundeep Kaur, PhD, Stephan Ehl, MD, Sebastian Hiller, PhD, Raif Geha, MD, Tony Roscioli, MD, PhD, Matthias Griese, MD, and Jana Pachlopnik Schmid, MD, PhD |
| Summary: | 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. |
|---|---|
| Item Description: | Gesehen am 17.11.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1097-6825 |
| DOI: | 10.1016/j.jaci.2021.03.045 |