Scientific article
Open access

Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency

Published inThe journal of allergy and clinical immunology, vol. 148, no. 2, p. 381-393
Publication date2021-08
First online date2021-04-17

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.

  • HLH-like disease
  • ZNFX1
  • Brain calcification
  • Interstitial lung disease
  • Leukoencephalopathy
  • Susceptibility to viral infections
  • Thrombotic microangiopathy
  • Type I interferon
  • Virally induced hepatitis
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • Child
  • Child, Preschool
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Inflammation / diagnostic imaging
  • Inflammation / genetics
  • Inflammation / immunology
  • Male
  • Primary Immunodeficiency Diseases / diagnostic imaging
  • Primary Immunodeficiency Diseases / genetics
  • Primary Immunodeficiency Diseases / immunology
  • Virus Diseases / diagnostic imaging
  • Virus Diseases / genetics
  • Virus Diseases / immunology
  • Whole Exome Sequencing
Citation (ISO format)
VAVASSORI, Stefano et al. Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency. In: The journal of allergy and clinical immunology, 2021, vol. 148, n° 2, p. 381–393. doi: 10.1016/j.jaci.2021.03.045
Main files (1)
Article (Accepted version)
ISSN of the journal0091-6749

Technical informations

Creation07/05/2022 7:08:00 AM
First validation07/05/2022 7:08:00 AM
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