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 - 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 -