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

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

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-β, 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.