Severe influenza pneumonitis in children with inherited TLR3 deficiency-Reference-Cited by-同舟云学术

Severe influenza pneumonitis in children with inherited TLR3 deficiency

Published:2019-06-19 Issue:9 Volume:216 Page:2038-2056
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Lim Hye Kyung¹²³^ORCID,Huang Sarah X.L.⁴⁵⁶,Chen Jie¹⁷^ORCID,Kerner Gaspard²³^ORCID,Gilliaux Olivier⁸⁹^ORCID,Bastard Paul²³^ORCID,Dobbs Kerry¹⁰^ORCID,Hernandez Nicholas¹,Goudin Nicolas¹¹^ORCID,Hasek Mary L.¹,García Reino Eduardo Javier¹,Lafaille Fabien G.¹,Lorenzo Lazaro²³^ORCID,Luthra Priya¹²¹³,Kochetkov Tatiana¹,Bigio Benedetta¹,Boucherit Soraya²³^ORCID,Rozenberg Flore¹⁴,Vedrinne Catherine¹⁵,Keller Michael D.¹⁶,Itan Yuval¹¹⁷¹⁸,García-Sastre Adolfo¹²¹³^ORCID,Celard Marie¹⁹,Orange Jordan S.²⁰,Ciancanelli Michael J.¹^ORCID,Meyts Isabelle²¹²²²³,Zhang Qian¹,Abel Laurent¹²³^ORCID,Notarangelo Luigi D.¹⁰^ORCID,Snoeck Hans-Willem⁴⁵,Casanova Jean-Laurent¹²³²⁴²⁵^ORCID,Zhang Shen-Ying¹²³^ORCID

Affiliation:

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

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.

Funder

National Center for Advancing Translational Sciences

National Institutes of Health

National Institute of Allergy and Infectious Diseases

National Institute of Neurological Disorders and Stroke

Cooperative Center on Human Immunology

Rockefeller University

Institut National de la Santé et de la Recherche Médicale

Paris Descartes University

French National Research Agency

Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence

Center for Research on Influenza Pathogenesis