Severe influenza pneumonitis in children with inherited TLR3 deficiency.,Journal of Experimental Medicine

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Severe influenza pneumonitis in children with inherited TLR3 deficiency.
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2019-06-19 , DOI: 10.1084/jem.20181621
Hye Kyung Lim _{1,

2,

3} , Sarah X L Huang _{4,

5,

6} , Jie Chen _{1,

7} , Gaspard Kerner _{2,

3} , Olivier Gilliaux _{8,

9} , Paul Bastard _{2,

3} , Kerry Dobbs ₁₀ , Nicholas Hernandez ₁ , Nicolas Goudin ₁₁ , Mary L Hasek ₁ , Eduardo Javier García Reino ₁ , Fabien G Lafaille ₁ , Lazaro Lorenzo _{2,

3} , Priya Luthra _{12,

13} , Tatiana Kochetkov ₁ , Benedetta Bigio ₁ , Soraya Boucherit _{2,

3} , Flore Rozenberg ₁₄ , Catherine Vedrinne ₁₅ , Michael D Keller ₁₆ , Yuval Itan _{1,

17,

18} , Adolfo García-Sastre _{12,

13} , Marie Celard ₁₉ , Jordan S Orange ₂₀ , Michael J Ciancanelli ₁ , Isabelle Meyts _{21,

22,

23} , Qian Zhang ₁ , Laurent Abel _{1,

2,

3} , Luigi D Notarangelo ₁₀ , Hans-Willem Snoeck _{4,

5} , Jean-Laurent Casanova _{1,

2,

3,

24,

25} , Shen-Ying Zhang _{2,

3,

26}

Affiliation

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR 1163, Paris, France.
Paris Descartes University, Imagine Institute, Paris, France.
Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY.
Department of Medicine, Columbia University Medical Center, New York, NY.
Center for Stem Cell and Regenerative Medicine, University of Texas Health Science Center at Texas, Houston, TX.
Department of Infectious Diseases, Shanghai Sixth Hospital, Shanghai Jiaotong University, Shanghai, China.
Laboratory of Experimental Medicine (ULB222), Medicine Faculty, Libre de Bruxelles University, Brussels, Belgium.
Department of Pediatrics, University Hospital Center of Charleroi, Charleroi, Belgium.
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Cell Imaging Platform Structure Fédérative de Recherche Necker, Institut National de la Santé et de la Recherche Médicale US 24, Paris, France.
Department of Microbiology, Global Health and Emerging Pathogens Institute, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY.
Virology, Cochin-Saint-Vincent de Paul Hospital, Paris Descartes University, Paris, France.
Department of Anesthesia and Intensive Care Medicine in Cardiovascular Surgery, Louis Pradel Cardiological Hospital, Lyon, France.
Division of Allergy and Immunology, Center for Cancer and Immunology Research, Children's National Health System, Washington, DC.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
National Center for Staphylococcus, Lyon Civil Hospital, Lyon, France.
Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
Laboratory for Inborn Errors of Immunity, Department of Immunology, Microbiology, and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium.
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
Precision Immunology Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Pediatric Immuno-Hematology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris, France.
Howard Hughes Medical Institute, New York, NY.
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY

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 (P554S 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-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 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.

中文翻译：

小儿遗传性TLR3缺乏症的严重流感性肺炎。

常染色体隐性IRF7和IRF9缺陷会损害I型和III型IFN免疫，并成为严重的流感性肺炎的基础。我们报告了三个无关的儿童，它们表现为急性呼吸窘迫综合征（IAV-ARDS），罕见的TLR3变体（两名患者为P554S，第三名为P680L）杂合，导致常染色体显性（AD）TLR3缺乏。AD TLR3缺乏可能通过削弱皮质神经元固有型I型IFN对HSV-1的免疫力而成为单纯疱疹病毒1（HSV-1）脑炎（HSE）的基础。TLR3突变的白细胞对IAV产生正常水平的IFN。相反，在IAV感染后，TLR3突变的成纤维细胞产生较低水平的IFN-β和-λ，并显示出更高的病毒易感性。此外，患者的iPSC衍生的肺上皮细胞（PEC）对IAV敏感。用IFN-α2b或IFN-λ1治疗可挽救该表型。因此，AD TLR3缺乏可能是通过削弱TLR3依赖的I型和/或III型IFN介导的PEC固有免疫力而成为IAV-ARDS的基础。对于IAV-ARDS和HSE，其临床表现并不完整，这与它们通常的零星特性是一致的。

更新日期：2019-09-03

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