Man Chun Leung, Laurent Abel, Bertrand Boisson, Jeffrey Danielson, Huie Jing, Susie S.Y. Huang, Vimel Rattina, Serkan Belkaya, Lisa S. Mathew, Nicholas Hernandez, Yanick J. Crow, Silvia Giliani, Stephen J. Elledge, Michael J. Ciancanelli, Yoann Rose, Damien Chaussabel, Lazaro Lorenzo-Diaz, Tanwir Habib, Isabelle Melki, Qian Zhang, Helen C. Su, Jean-Laurent Casanova, Shen-Ying Zhang, Marie-Noëlle Lebras, Luigi D. Notarangelo, Nico Marr, Stéphanie Boisson-Dupuis, Mathieu P Rodero, Scott Drutman, Naoki Kitabayashi, Tomasz Kula, Cécile Dumaine, Anais Boulai, Stéphane Blanche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], Imagine - Institut des maladies génétiques (IMAGINE - U1163), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
We report a child with inherited, complete IRF9 deficiency who suffered from life-threatening influenza pneumonitis. IRF9 deficiency disrupts the activation of ISGF3 and impairs but does not abolish cellular responses to type I IFNs, as some ISGs are induced., 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.