Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 7, Issue 307, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aac4227
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Funding
- Academy of Medical Sciences [AMS-SGCL11]
- British Infection Association
- UK NIH Research (NIHR)
- Universiti Sains Malaysia Fellowship
- Sir Jules Thorn Trust [12/JTA]
- Wellcome Trust [101788/Z/13/Z]
- Medical Research Council-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing
- NIHR Newcastle Biomedical Research Centre
- UCLH/UCL NIHR Biomedical Research Centre
- FP7 PATHSEEK grant
- NIHR
- MRC [G0801975] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [AMS-SGCL11-Duncan] Funding Source: researchfish
- Medical Research Council [G0801975] Funding Source: researchfish
- National Institute for Health Research [CL-2013-01-003] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [12JTA] Funding Source: researchfish
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Type I interferon (IFN-alpha/beta) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-alpha/beta in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-alpha/beta receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-alpha/beta. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-alpha/beta responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-alpha/beta in human antiviral immunity.
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