1. Severe influenza pneumonitis in children with inherited TLR3 deficiency
- Author
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Mary Hasek, Isabelle Meyts, Michael D. Keller, Flore Rozenberg, Fabien G. Lafaille, Priya Luthra, Lazaro Lorenzo, Marie Celard, Jie Chen, Eduardo J. Garcia Reino, Tatiana Kochetkov, Laurent Abel, Catherine Vedrinne, Yuval Itan, Olivier Gilliaux, Hye Kyung Lim, Soraya Boucherit, Benedetta Bigio, Jordan S. Orange, Nicholas Hernandez, Nicolas Goudin, Paul Bastard, Sarah X.L. Huang, Hans-Willem Snoeck, Jean-Laurent Casanova, Michael J. Ciancanelli, Gaspard Kerner, Kerry Dobbs, Shen-Ying Zhang, Luigi D. Notarangelo, Qian Zhang, and Adolfo García-Sastre
- Subjects
0301 basic medicine ,Male ,viruses ,NF-KAPPA-B ,Inheritance Patterns ,STAT2 DEFICIENCY ,Research & Experimental Medicine ,medicine.disease_cause ,RIG-I ,0302 clinical medicine ,Fatal Outcome ,Loss of Function Mutation ,Influenza A virus ,Immunology and Allergy ,Child ,Lung ,Research Articles ,virus diseases ,hemic and immune systems ,Penetrance ,3. Good health ,VIRUS ENCEPHALITIS ,Protein Transport ,Medicine, Research & Experimental ,Child, Preschool ,Female ,Life Sciences & Biomedicine ,Encephalitis ,STRUCTURAL BASIS ,Heterozygote ,HERPES-SIMPLEX ENCEPHALITIS ,Immunology ,Induced Pluripotent Stem Cells ,Mutation, Missense ,chemical and pharmacologic phenomena ,DOUBLE-STRANDED-RNA ,PANDEMIC INFLUENZA ,Article ,03 medical and health sciences ,Immunity ,Influenza, Human ,medicine ,Humans ,Alleles ,Pneumonitis ,Science & Technology ,business.industry ,TOLL-LIKE RECEPTOR-3 ,Infant, Newborn ,Infant ,Heterozygote advantage ,Epithelial Cells ,Pneumonia ,Fibroblasts ,medicine.disease ,Toll-Like Receptor 3 ,030104 developmental biology ,Poly I-C ,IRF7 ,Interferons ,business ,030217 neurology & neurosurgery ,GROWTH-RETARDATION - Abstract
The authors report three unrelated children with inherited TLR3 deficiency, impaired TLR3-dependent, IFN-α/β– and/or -λ–mediated, pulmonary epithelial cell–intrinsic immunity to influenza A virus, and life-threatening influenza pneumonitis., 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.
- Published
- 2018