期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 31, 页码 8342-8347出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1704259114
关键词
respiratory syncytial virus; rhinovirus; IFIH1; RIG-I-like receptor family; severe pediatric infectious disease
资金
- Swiss National Science Foundation [PP00P3_133703, PP00P3_157529]
- Swiss National Science Foundation (SNF) [PP00P3_133703, PP00P3_157529] Funding Source: Swiss National Science Foundation (SNF)
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-beta, 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.
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