Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 9, Pages 2038-2056Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20181621
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Funding
- National Center for Advancing Translational Sciences, National Institutes of Health, Clinical and Translational Science Award program [UL1TR001866]
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01AI088364, R21AI137371]
- National Institute of Neurological Disorders and Stroke, National Institutes of Health [R01NS072381]
- Cooperative Center on Human Immunology, National Institute of Allergy and Infectious Diseases [U19AI111825]
- Rockefeller University
- French National Research Agency under the Investments for the future program [ANR-10-IAHU-01]
- Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
- Institut National de la Sante et de la Recherche Medicale, Paris Descartes University
- IEIHSEER [ANR-14-CE14-0008-01]
- Center for Research on Influenza Pathogenesis, an National Institute of Allergy and Infectious Diseases [HHSN272201400008C]
- St. Giles Foundation
- Thrasher Research Fund
- Medical Scientist Training Program grant from the National Institute of General Medical Sciences, National Institutes of Health [T32GM007739]
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen project [G0C8517N]
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001222] Funding Source: NIH RePORTER
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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 (P5545 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-beta and -lambda, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-a2b or IFN-lambda 1 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.
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