Human IFNAR2 deficiency: Lessons for antiviral immunity
Science Translational Medicine • 30 Sep 2015 • Vol 7, Issue 307 • p. 307ra154 • DOI: 10.1126/scitranslmed.aac4227
Type I interferons in antiviral defense
Type I interferons have been shown in animal models to provide a critical antiviral defense, but supporting data in humans have been lacking. Now, Duncan et al. report the case of a child and a newborn sibling with a homozygous mutation in the high-affinity interferon-α/β receptor (IFNAR2), which prevented cells from responding to IFN-α/β. The previously healthy proband developed fatal encephalitis after exposure to the live attenuated measles, mumps, and rubella vaccine. Reconstituting the proband’s cells with IFNAR2 restored control of IFN-attenuated viruses. These data support an essential role for IFN-α/β in antiviral immunity.
Abstract
Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β 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-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband’s cells with wild-type IFNAR2 restored IFN-α/β 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-α/β in human antiviral immunity.
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Supplementary Material
Summary
Case Summary S1
Fig. S1. Antiviral activity of IFN-γ.
Fig. S2. IFN-β signaling.
Fig. S3. Failure of ISG induction in patient II.2.
Fig. S4. IFNAR2 expression in U5A cells.
Table S1. Detection of vaccine strain viruses and HHV6 by PCR or viral culture in patient II.1.
Table S2. Antibody responses to MMR in patient II.1.
Table S3. Immunological and hematological parameters from patient II.1.
Source data (immunoblots).
Data set S1. IFN-α microarray.
Data set S2. IFN-β microarray.
Data set S3. IFN-γ microarray.
Resources
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Information & Authors
Information
Published In
Science Translational Medicine
Volume 7 • Issue 307 • 30 September 2015
Pages: 307ra154
History
Received: 24 April 2015
Accepted: 24 July 2015
Copyright
Copyright © 2015, American Association for the Advancement of Science.
