TY - JOUR
T1 - Severe viral respiratory infections in children with IFIH1 loss-of-function mutations
AU - Asgari, Samira
AU - Schlapbach, Luregn J.
AU - Anchisi, Stéphanie
AU - Hammer, Christian
AU - Bartha, Istvan
AU - Junier, Thomas
AU - Mottet-Osman, Geneviève
AU - Posfay-Barbe, Klara M.
AU - Longchamp, David
AU - Stocker, Martin
AU - Cordey, Samuel
AU - Kaiser, Laurent
AU - Riedel, Thomas
AU - Kenna, Tony
AU - Long, Deborah
AU - Schibler, Andreas
AU - Telenti, Amalio
AU - Tapparel, Caroline
AU - McLaren, Paul J.
AU - Garcin, Dominique
AU - Fellay, Jacques
N1 - Funding Information:
We express our sincere appreciation to all study participants and their families for their participation and support. We thank Deon Venter and Marc Vipond, Mater Pathology, Mater Health Services, Brisbane, as well as Patricia Keith, Institute for Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia, for their help in sample processing and sampling logistics; Mark Peeples (Columbus, OH) for sharing rRSV-GFP, and Jean-François Eléouët (Institut National de la Recherche Agronomique, Jouy-en-Josas, France) for sharing rRSV- mCherry. mCherry. This study was funded by Swiss National Science Foundation Grants PP00P3_133703 and PP00P3_157529 (to J.F.).
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - IFIH1
KW - RIG-I-like receptor family severe pediatric infectious disease
KW - Respiratory syncytial virus
KW - Rhinovirus
UR - http://www.scopus.com/inward/record.url?scp=85026787138&partnerID=8YFLogxK
U2 - 10.1073/pnas.1704259114
DO - 10.1073/pnas.1704259114
M3 - Article
C2 - 28716935
AN - SCOPUS:85026787138
SN - 0027-8424
VL - 114
SP - 8342
EP - 8347
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -