Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Samira Asgari, Luregn J. Schlapbach, Stéphanie Anchisi, Christian Hammer, Istvan Bartha, Thomas Junier, Geneviève Mottet-Osman, Klara M. Posfay-Barbe, David Longchamp, Martin Stocker, Samuel Cordey, Laurent Kaiser, Thomas Riedel, Tony Kenna, Deborah Long, Andreas Schibler, Amalio Telenti, Caroline Tapparel, Paul J. McLaren, Dominique GarcinJacques Fellay

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-ß, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.

Original languageEnglish
Pages (from-to)8342-8347
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number31
DOIs
StatePublished - 1 Aug 2017
Externally publishedYes

Keywords

  • IFIH1
  • RIG-I-like receptor family severe pediatric infectious disease
  • Respiratory syncytial virus
  • Rhinovirus

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