STAT2 deficiency and susceptibility to viral illness in humans

Sophie Hambleton*, Stephen Goodbourn, Dan Frushard Young, Paul Dickinson, Siti M. B. Mohamad, Manoj Valappil, Naomi McGovern, Andrew J. Cant, Scott J. Hackett, Peter Ghazal, Neil V. Morgan, Richard Edward Randall

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

128 Citations (Scopus)

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 languageEnglish
Pages (from-to)3053-3058
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
Publication statusPublished - 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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