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

被引：155

作者：

Hernandez, Nicholas ^{[1
]}

Melki, Isabelle ^{[2
,3
,4
]}

Jing, Huie ^{[5
]}

Habib, Tanwir ^{[6
]}

Huang, Susie S. Y. ^{[6
]}

Danielson, Jeffrey ^{[5
]}

Kula, Tomasz ^{[7
,8
]}

Drutman, Scott ^{[1
]}

Belkaya, Serkan ^{[1
]}

Rattina, Vimel ^{[9
,10
]}

Lorenzo-Diaz, Lazaro ^{[9
,10
]}

Boulai, Anais ^{[4
]}

Rose, Yoann ^{[4
]}

Kitabayashi, Naoki ^{[4
]}

Rodero, Mathieu P. ^{[4
]}

Dumaine, Cecile ^{[2
,3
]}

Blanche, Stephane ^{[2
]}

Lebras, Marie-Noelle ^{[11
]}

Leung, Man Chun ^{[6
]}

Mathew, Lisa Sara ^{[6
]}

Boisson, Bertrand ^{[1
,9
,10
]}

Zhang, Shen-Ying ^{[1
,9
,10
]}

Boisson-Dupuis, Stephanie ^{[1
,9
,10
]}

Giliani, Silvia ^{[1
,12
]}

Chaussabel, Damien ^{[6
]}

Notarangelo, Luigi D. ^{[5
]}

Elledge, Stephen J. ^{[7
,8
,13
]}

Ciancanelli, Michael J. ^{[1
]}

Abel, Laurent ^{[1
,9
,10
]}

Zhang, Qian ^{[1
]}

Marr, Nico ^{[6
]}

Crow, Yanick J. ^{[4
,10
,14
,15
]}

Su, Helen C. ^{[5
]}

Casanova, Jean-Laurent ^{[1
,2
,9
,10
,16
]}

机构：

[1] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA

[2] Necker Hosp Sick Children, AP HP, Pediat Immunol Hematol & Rheumatol Unit, Paris, France

[3] Robert Debre Hosp, AP HP, Infect Dis & Internal Med Dept, Gen Pediat, Paris, France

[4] INSERM, UMR 1163, Lab Neurogenet & Neuroinflammat, Paris, France

[5] NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[6] Sidra Med, Div Translat Med, Doha, Qatar

[7] Brigham & Womens Hosp, Dept Genet, Div Genet, 75 Francis St, Boston, MA 02115 USA

[8] Harvard Med Sch, Boston, MA USA

[9] INSERM, U1163, Lab Human Genet Infect Dis, Necker Branch, Paris, France

[10] Paris Descartes Univ, Imagine Inst, Paris, France

[11] Robert Debre Hosp, AP HP, Infect Dis & Internal Med Dept, Pediat Pulmonol, Paris, France

[12] Univ Brescia, Angelo Nocivelli Inst Mol Med, Brescia, Italy

[13] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA USA

[14] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[15] Necker Hosp Sick Children, AP HP, Dept Genet, Paris, France

[16] Howard Hughes Med Inst, New York, NY USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2018年 / 215卷 / 10期

基金：

美国国家卫生研究院; 欧洲研究理事会;

关键词：

INTERFERON REGULATORY FACTOR; INFLAMMATORY-BOWEL-DISEASE; TRANSCRIPTION FACTOR; PRIMARY IMMUNODEFICIENCIES; PANDEMIC INFLUENZA; NONSENSE MUTATION; STAT2; DEFICIENCY; STRUCTURAL BASIS; VIRUS-INFECTION; DENDRITIC CELLS;

D O I：

10.1084/jem.20180628

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：2567 / 2585

页数：19

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