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.

Nicholas Hernandez ¹, Isabelle Melki ² ³ ⁴, Huie Jing ⁵, Tanwir Habib ⁶, Susie S Y Huang ⁶, Jeffrey Danielson ⁵, Tomasz Kula ⁷, Scott Drutman ¹, Serkan Belkaya ¹, Vimel Rattina ⁸ ⁹, Lazaro Lorenzo-Diaz ⁸ ⁹, Anais Boulai ⁴, Yoann Rose ⁴, Naoki Kitabayashi ⁴, Mathieu P Rodero ⁴, Cecile Dumaine ² ³, Stéphane Blanche ², Marie-Noëlle Lebras ¹⁰, Man Chun Leung ⁶, Lisa Sara Mathew ⁶, Bertrand Boisson ¹ ⁸ ⁹, Shen-Ying Zhang ¹ ⁸ ⁹, Stephanie Boisson-Dupuis ¹ ⁸ ⁹, Silvia Giliani ¹¹, Damien Chaussabel ⁶, Luigi D Notarangelo ⁵, Stephen J Elledge ⁷ ¹², Michael J Ciancanelli ¹, Laurent Abel ¹ ⁸ ⁹, Qian Zhang ¹, Nico Marr ⁶, Yanick J Crow ⁴ ⁹ ¹³ ¹⁴, Helen C Su ⁵, Jean-Laurent Casanova ¹⁵ ² ⁸ ⁹ ¹⁶

Affiliations

1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
2 Pediatric Immunology-Hematology and Rheumatology Unit, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France.
3 General Pediatrics, Infectious Disease and Internal Medicine Department, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Paris, France.
4 Laboratory of Neurogenetics and Neuroinflammation, Institut National de la Santé et de la Recherche Médicale UMR 1163, Paris, France.
5 Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
6 Division of Translational Medicine, Sidra Medicine, Doha, Qatar.
7 Division of Genetics, Department of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
8 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France.
9 Paris Descartes University, Imagine Institute, Paris, France.
10 Pediatric Pulmonology, Infectious Disease and Internal Medicine Department, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Paris, France.
11 Angelo Nocivelli Institute for Molecular Medicine, University of Brescia, Brescia, Italy.
12 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA.
13 Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
14 Department of Genetics, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France.
15 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY [email protected].
16 Howard Hughes Medical Institute, New York, NY.

PMID: 30143481 DOI: 10.1084/jem.20180628

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 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.

Name
Email *

	Sorry, but the email address you supplied was invalid.