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Abstract
Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. We hypothesized that a primary defect of innate antiviral immunity was responsible for unusually severe viral illness in two siblings; the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection. Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein. Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells. Subsequently, other family members were identified with the same genetic lesion. Despite documented infection by known viral pathogens, some of which have been more severe than normal, surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities. These findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.
Original language | English |
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Pages (from-to) | 3053-3058 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 110 |
Issue number | 8 |
DOIs | |
Publication status | Published - 19 Feb 2013 |
Keywords
- TLR3 DEFICIENCY
- IFN-BETA
- INBORN-ERRORS
- measles vaccine
- TARGETED DISRUPTION
- SIGNALING PATHWAY
- rare diseases
- ALPHA/BETA-INTERFERON
- V-PROTEIN
- VIRUS ENCEPHALITIS
- HERPES-SIMPLEX ENCEPHALITIS
- viruses
- HOST-DEFENSE
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Dive into the research topics of 'STAT2 deficiency and susceptibility to viral illness in humans'. Together they form a unique fingerprint.Projects
- 1 Finished
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The Interaction of paramyxoviruses: The interaction of paramyxoviruses with the interferon system
Randall, R. E. (PI)
1/04/09 → 31/03/14
Project: Standard