Title | Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Hernandez N, Melki I, Jing H, Habib T, S Y Huang S, Danielson J, Kula T, Drutman S, Belkaya S, Rattina V, Lorenzo-Diaz L, Boulai A, Rose Y, Kitabayashi N, Rodero MP, Dumaine C, Blanche S, Lebras M-N, Leung MChun, Mathew LSara, Boisson B, Zhang S-Y, Boisson-Dupuis S, Giliani S, Chaussabel D, Notarangelo LD, Elledge SJ, Ciancanelli MJ, Abel L, Zhang Q, Marr N, Crow YJ, Su HC, Casanova J-L |
Journal | J Exp Med |
Volume | 215 |
Issue | 10 |
Pagination | 2567-2585 |
Date Published | 2018 10 01 |
ISSN | 1540-9538 |
Keywords | Alleles, Female, Homozygote, Humans, Infant, Influenza, Human, Interferon alpha-2, Interferon-Stimulated Gene Factor 3, gamma Subunit, Orthomyxoviridae, Pneumonia, Viral |
Abstract | 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 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. |
DOI | 10.1084/jem.20180628 |
Alternate Journal | J. Exp. Med. |
PubMed ID | 30143481 |
PubMed Central ID | PMC6170168 |
Grant List | R21 AI137371 / AI / NIAID NIH HHS / United States T32 GM066699 / GM / NIGMS NIH HHS / United States UL1 TR001866 / TR / NCATS NIH HHS / United States U19 AI111825 / AI / NIAID NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
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