Header

UZH-Logo

Maintenance Infos

Multisystem Inflammation and Susceptibility to Viral infections in Human ZNFX1 Deficiency


Abstract

BACKGROUND

The 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-strand RNA sensor that restricts the replication of RNA viruses in mice. ZNFX1's role 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, as well as renal and lung disease.

METHODS

Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, post-transcriptional 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 ISGs mRNA and was associated with poorer clearance of virus 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.

Abstract

BACKGROUND

The 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-strand RNA sensor that restricts the replication of RNA viruses in mice. ZNFX1's role 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, as well as renal and lung disease.

METHODS

Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, post-transcriptional 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 ISGs mRNA and was associated with poorer clearance of virus 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.

Statistics

Citations

Dimensions.ai Metrics
33 citations in Web of Science®
35 citations in Scopus®
Google Scholar™

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Language:German
Date:1 August 2021
Deposited On:27 Apr 2021 15:33
Last Modified:25 Apr 2024 01:36
Publisher:Elsevier
ISSN:0091-6749
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jaci.2021.03.045
PubMed ID:33872655
Full text not available from this repository.