The genetics of severe illness in children with the common cold
EPFL scientists have discovered gene variants that make children life-threateningly susceptible to common-cold viruses.
Although most children can handle viral respiratory infections like the common cold, about 2% of children become sick enough to require hospitalization. There are some known risk factors for this, but severe illness still affects 1 in 1000 previously healthy kids. EPFL scientists have now discovered an underlying cause: gene variants that stop or reduce the production of interferon beta, a protein that activates the child’s innate immune response to respiratory viruses. The work is published in PNAS.
Severe respiratory illness due to viral infection is rare but can be life threatening to children, especially in places without access to modern medical care. This is a global problem since virtually everyone will contract common-cold viruses such as human rhinoviruses (HRV) and human respiratory syncytial viruses (HRSV) before the age of one.
The problem is exacerbated by the fact that we don’t actually have a biological explanation for this extreme susceptibility. A number of biological, socio-economic and environmental risk factors are known to increase susceptibility to severe infection, such as premature birth, chronic diseases, and immunosuppression. Still, approximately 1 out of 1000 children without any of these risk factors falls severely sick when contracting the common cold.
The lab of Jacques Fellay at EPFL carried out a genomic analysis on 120 previously healthy children that had been admitted to pediatric intensive care units with respiratory failure due to infection with HRV or HRSV.
The project, led by PhD student Samira Asgari, combined exome sequencing, transcriptomic analysis, and in vitro functional testing to look for genetic variants that make children extremely susceptible to the viruses.
Asgari found that several of the children carried what is known as a “loss-of-function" variant in a gene called IFIH1. The gene produces a protein that acts a intracellular sensor for genetic material from infecting viruses. When it detects them, the protein triggers the production of interferon beta, which plays a key role in activating the immune response against the invading pathogen.
By disrupting the production of interferon beta, the mutation blocks the initial, “innate” immune response to HRV and HRSV. Without an early immune response, the children’s systems become overwhelmed by the virus, and without immediate medical care they are at high risk of dying from the infection.
The scientists were able to confirm their discovery on genetically modified human cells. Given their lethality, the IFIH1 variants are rare, but they still affect a considerable number of children in the world. “This discovery suggests new preventive or therapeutic strategies,” says Asgari, who is now pursuing her postdoctoral research at Harvard’s Brigham and Women’s Hospital. “Susceptible children can be identified before they are infected, and specific prevention efforts can be started. Also, if the lack of interferon beta prevents the innate immune reaction from kicking in, it is tempting to imagine that doctors could administer it to the kids.”
Swiss Institute of Bioinformatics
Mater Research Institute
University of Geneva
Eötvos Loránd University
Geneva University Hospital
Lausanne University Hospital
Lucerne Children’s Hospital
University of Bern
Queensland University of Technology
University of Queensland
Human Longevity, Inc.
University of Manitoba
Swiss National Science Foundation
Samira Asgari, Luregn Schlapbach, Stéphanie Anchisi, Christian Hammer, István Bartha, Thomas Junier, Geneviève Mottet-Osman, Klara Posfay Barbe, David Longchamp, Martin Stocker, Samuel Cordey, Laurent Kaiser, Thomas Riedel, Tony Kenna, Deborah Long, Andreas Schibler, Amalio Telenti, Caroline Tapparel, Paul McLaren, Dominique Garcin, Jacques Fellay. Severe viral respiratory infections in children with IFIH1 loss-of-function mutations.PNAS 17 July 2017. DOI: 10.1073/pnas.1704259114