Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

J Exp Med. 2018 Oct 1;215(10):2567-2585. doi: 10.1084/jem.20180628. Epub 2018 Aug 24.


Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Female
  • Homozygote*
  • Humans
  • Infant
  • Influenza, Human* / genetics
  • Influenza, Human* / immunology
  • Influenza, Human* / pathology
  • Interferon alpha-2 / genetics
  • Interferon alpha-2 / immunology
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / deficiency*
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / immunology
  • Orthomyxoviridae / immunology*
  • Pneumonia, Viral* / genetics
  • Pneumonia, Viral* / immunology
  • Pneumonia, Viral* / pathology


  • IRF9 protein, human
  • Interferon alpha-2
  • Interferon-Stimulated Gene Factor 3, gamma Subunit