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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
Published on: December 10, 2013
Severe viral respiratory infections in children with IFIH1 loss-of-function mutations
Samira Asgari1,2, Luregn J Schlapbach3,4,5, Stéphanie Anchisi6
1Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, 1015, Switzerland.
Insights
Genetic variants in IFIH1, which senses viral RNA, can cause severe respiratory infections in children. This IFIH1 deficiency leads to primary immunodeficiency, increasing susceptibility to common RNA viruses.
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- Viral respiratory infections are typically mild but can be life-threatening in children.
- A genetic basis for severe, life-threatening viral respiratory infections in healthy children is investigated.
Purpose of the Study:
- To identify genetic causes of severe respiratory viral infections in previously healthy children.
Main Methods:
- Exome and transcriptome sequencing were used to analyze 120 children with severe viral respiratory illness.
- Functional testing of identified IFIH1 variants was performed.
Main Results:
- Three rare loss-of-function variants in the IFIH1 gene were identified.
- These IFIH1 variants result in proteins with impaired IFN-β induction, reduced stability, and lack of ATPase activity.
- IFIH1 was shown to restrict human respiratory syncytial virus and rhinovirus replication in vitro.
Conclusions:
- IFIH1 deficiency causes primary immunodeficiency characterized by extreme susceptibility to common respiratory RNA viruses.
- Genetic defects in viral sensing pathways can lead to severe disease from common viruses.
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-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.
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