TY - JOUR
T1 - Severe influenza pneumonitis in children with inherited TLR3 deficiency
AU - Lim, Hye Kyung
AU - Huang, Sarah X.L.
AU - Chen, Jie
AU - Kerner, Gaspard
AU - Gilliaux, Olivier
AU - Bastard, Paul
AU - Dobbs, Kerry
AU - Hernandez, Nicholas
AU - Goudin, Nicolas
AU - Hasek, Mary L.
AU - Reino, Eduardo Javier García
AU - Lafaille, Fabien G.
AU - Lorenzo, Lazaro
AU - Luthra, Priya
AU - Kochetkov, Tatiana
AU - Bigio, Benedetta
AU - Boucherit, Soraya
AU - Rozenberg, Flore
AU - Vedrinne, Catherine
AU - Keller, Michael D.
AU - Itan, Yuval
AU - García-Sastre, Adolfo
AU - Celard, Marie
AU - Orange, Jordan S.
AU - Ciancanelli, Michael J.
AU - Meyts, Isabelle
AU - Zhang, Qian
AU - Abel, Laurent
AU - Notarangelo, Luigi D.
AU - Snoeck, Hans Willem
AU - Casanova, Jean Laurent
AU - Zhang, Shen Ying
N1 - Funding Information:
UL1TR001866), National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant nos. R01AI088364 and R21AI137371), National Institute of Neurological Disorders and Stroke, National Institutes of Health (grant no. R01NS072381), Cooperative Center on Human Immunology, National Institute of Allergy and Infectious Diseases (grant no. U19AI111825), Rockefeller University, Institut National de la Santé et de la Recherche Médicale, Paris Descartes University, the French National Research Agency under the “Investments for the future” program (grant no. ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (grant no. ANR-10-LABX-62-IBEID), IEIHSEER (grant no. ANR-14-CE14-0008-01), the Center for Research on Influenza Pathogenesis, an National Institute of Allergy and Infectious Diseases-funded Center of Excellence for Influenza Research and Surveillance contract (HHSN272201400008C), the St. Giles Foundation, and the Thrasher Research Fund. N. Hernandez was supported by the Medical Scientist Training Program grant from the National Institute of General Medical Sciences, National Institutes of Health, under award no. T32GM007739. I. Meyts was funded by Fonds voor Wetenschappelijk Onderzoek Vlaanderen project no. G0C8517N. K. Dobbs and L.D. Nota-rangelo are supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The authors declare no competing financial interests.
Funding Information:
The work was funded in part by the National Center for Advancing Translational Sciences, National Institutes of Health, Clinical and Translational Science Award program (grant no.
Publisher Copyright:
© 2019 Lim et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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 IFNα2b 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.
AB - 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 IFNα2b 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.
UR - http://www.scopus.com/inward/record.url?scp=85071616765&partnerID=8YFLogxK
U2 - 10.1084/jem.20181621
DO - 10.1084/jem.20181621
M3 - Article
C2 - 31217193
AN - SCOPUS:85071616765
SN - 0022-1007
VL - 216
SP - 2038
EP - 2056
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
ER -