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J Exp Med. 2019 Jun 19. pii: jem.20181621. doi: 10.1084/jem.20181621. [Epub ahead of print]

Severe influenza pneumonitis in children with inherited TLR3 deficiency.

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
2
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR 1163, Paris, France.
3
Paris Descartes University, Imagine Institute, Paris, France.
4
Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY.
5
Department of Medicine, Columbia University Medical Center, New York, NY.
6
Center for Stem Cell and Regenerative Medicine, University of Texas Health Science Center at Texas, Houston, TX.
7
Department of Infectious Diseases, Shanghai Sixth Hospital, Shanghai Jiaotong University, Shanghai, China.
8
Laboratory of Experimental Medicine (ULB222), Medicine Faculty, Libre de Bruxelles University, Brussels, Belgium.
9
Department of Pediatrics, University Hospital Center of Charleroi, Charleroi, Belgium.
10
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
11
Cell Imaging Platform Structure Fédérative de Recherche Necker, Institut National de la Santé et de la Recherche Médicale US 24, Paris, France.
12
Department of Microbiology, Global Health and Emerging Pathogens Institute, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
13
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY.
14
Virology, Cochin-Saint-Vincent de Paul Hospital, Paris Descartes University, Paris, France.
15
Department of Anesthesia and Intensive Care Medicine in Cardiovascular Surgery, Louis Pradel Cardiological Hospital, Lyon, France.
16
Division of Allergy and Immunology, Center for Cancer and Immunology Research, Children's National Health System, Washington, DC.
17
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
18
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
19
National Center for Staphylococcus, Lyon Civil Hospital, Lyon, France.
20
Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
21
Laboratory for Inborn Errors of Immunity, Department of Immunology, Microbiology, and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium.
22
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
23
Precision Immunology Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
24
Pediatric Immuno-Hematology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris, France.
25
Howard Hughes Medical Institute, New York, NY.
26
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY shzh289@rockefeller.edu.
#
Contributed equally

Abstract

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.

PMID:
31217193
DOI:
10.1084/jem.20181621

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