Severe influenza pneumonitis in children with inherited TLR3 deficiency

被引：146

作者：

Lim, Hye Kyung ^{[1
,2
,3
]}

Huang, Sarah X. L. ^{[5
,6
]}

Chen, Jie ^{[1
,7
]}

Kerner, Gaspard ^{[2
,3
]}

Gilliaux, Olivier ^{[8
,9
]}

Bastard, Paul ^{[2
,3
]}

Dobbs, Kerry ^{[10
]}

Hernandez, Nicholas ^{[1
]}

Goudin, Nicolas ^{[11
]}

Hasek, Mary L. ^{[1
]}

Reino, Eduardo Javier Garcia ^{[1
]}

Lafaille, Fabien G. ^{[1
]}

Lorenzo, Lazaro ^{[2
,3
]}

Luthra, Priya ^{[12
,13
]}

Kochetkov, Tatiana ^{[1
]}

Bigio, Benedetta ^{[1
]}

Boucherit, Soraya ^{[2
,3
]}

Rozenberg, Flore ^{[14
]}

Vedrinne, Catherine ^{[15
]}

Keller, Michael D. ^{[16
]}

Itan, Yuval ^{[1
,17
,18
]}

Garcia-Sastre, Adolfo ^{[12
]}

Celard, Marie ^{[19
]}

Orange, Jordan S. ^{[20
]}

Ciancanelli, Michael J. ^{[1
]}

Meyts, Isabelle ^{[21
,22
,23
,24
]}

Zhang, Qian ^{[1
]}

Abel, Laurent ^{[1
,2
,3
]}

Notarangelo, Luigi D. ^{[10
]}

Snoeck, Hans-Willem ^{[1
,4
]}

Casanova, Jean-Laurent ^{[1
,2
,3
,25
,26
]}

Zhang, Shen-Ying ^{[1
,2
,3
]}

机构：

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

[2] INSERM UMR 1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France

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

[4] Columbia Univ, Columbia Ctr Translat Immunol, Med Ctr, New York, NY USA

[5] Columbia Univ, Dept Med, Med Ctr, New York, NY USA

[6] Univ Texas Hlth Sci Ctr, Ctr Stem Cell & Regenerat Med, Houston, TX USA

[7] Paris Descartes Univ, Paris, France

[8] Univ Libre Bruxelles, Fac Med, Lab Expt Med ULB222, Brussels, Belgium

[9] Univ Hosp Ctr Charleroi, Dept Pediat, Charleroi, Belgium

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

[11] INSERM US 24, Cell Imaging Platform Struct Fed Nerat Platiamwy, Paris, France

[12] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Global Hlth & Emerging Pathogens Inst, Dept Microbiol, New York, NY 10029 USA

[13] Icahn Sch Med Mt Sinai, Div Infect Dis, Dept Med, New York, NY USA

[14] Paris Descartes Univ, Cochin St Vincent Paul Hosp, Virol, Paris, France

[15] Louis Pradel Cardiol Hosp, Dept Anesthesia & Intens Care Med Cardiovasc Surg, Lyon, France

[16] Childrens Natl Hlth Syst, Ctr Canc & Immunol Res, Div Allergy & Immunol, Washington, DC USA

[17] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[18] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[19] Lyon Civil Hosp, Natl Ctr Staphylococcus, Lyon, France

[20] Childrens Hosp, Baylor Coll Med, Houston, TX USA

[21] Katholieke Univ Leuven, Dept Immunol Microbiol & Transplantat, Lab Inborn Errors Immun, Leuven, Belgium

[22] Univ Hosp Leuven, Dept Pediat, Leuven, Belgium

[23] Icahn Sch Med Mt Sinai, Precis Immunol Inst, New York, NY 10029 USA

[24] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[25] Necker Hosp Sick Children, AP HP, Pediat Immuno Hematol Unit, Paris, France

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

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2019年 / 216卷 / 09期

基金：

美国国家卫生研究院;

关键词：

TOLL-LIKE RECEPTOR-3; DOUBLE-STRANDED-RNA; HERPES-SIMPLEX ENCEPHALITIS; NF-KAPPA-B; INBORN-ERRORS; RIG-I; PANDEMIC INFLUENZA; VIRUS ENCEPHALITIS; GROWTH-RETARDATION; STAT2; DEFICIENCY;

D O I：

10.1084/jem.20181621

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：

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P5545 in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-beta and -lambda, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-a2b or IFN-lambda 1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

引用

页码：2038 / 2056

页数：19

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