Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 215, Issue 10, Pages 2567-2585Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20180628
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Funding
- Center for Research Resources [UL1TR001866]
- National Center for Advancing Translational Sciences [UL1TR001866]
- National Institute of Allergy and Infectious Diseases for Cooperative Center on Human Immunology at The Rockefeller University [U19AI111825]
- National Institute of Allergy and Infectious Diseases [R21AI137371]
- St. Giles Foundation
- French National Research Agency under the Investments for the Future program [ANR-10-IAHU-01]
- Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases [ANR- 10-LABX-62-IBEID]
- Institut National de la Sante et de la Recherche Medicale
- Paris Descartes University
- Intramural Research Program at the National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- Qatar National Research Fund [NPRP9-251-3-045]
- Fondation Bettencourt Schueller through the Programme Sante-Sciences MD/PhD of the Imagine Institute
- Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health [T32GM007739]
- European Research Council [GA 309449]
- Qatar National Research Fund's Paths Toward Personalized Medicine Program grant [PPM1-1220-150017]
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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-alpha 2b. The transcriptome induced by IFN-alpha 2b 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.
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