Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis-Reference-Cited by-同舟云学术

Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis

Published:2021-11-02 Issue:12 Volume:218 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Chen Jie¹²^ORCID,Jing Huie³^ORCID,Martin-Nalda Andrea⁴⁵⁶^ORCID,Bastard Paul¹⁷⁸^ORCID,Rivière Jacques G.⁴⁵⁶^ORCID,Liu Zhiyong¹^ORCID,Colobran Roger⁶⁹¹⁰^ORCID,Lee Danyel¹⁷⁸^ORCID,Tung Wesley³^ORCID,Manry Jeremy⁷⁸^ORCID,Hasek Mary¹^ORCID,Boucherit Soraya⁷⁸^ORCID,Lorenzo Lazaro⁷⁸^ORCID,Rozenberg Flore¹¹^ORCID,Aubart Mélodie⁷⁸¹²^ORCID,Abel Laurent¹⁷⁸^ORCID,Su Helen C.³^ORCID,Soler Palacin Pere⁴⁵⁶^ORCID,Casanova Jean-Laurent¹⁷⁸¹³^ORCID,Zhang Shen-Ying¹⁷⁸^ORCID

Affiliation:

1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY

2. Department of Infectious Diseases, Shanghai Sixth Hospital, Shanghai Jiaotong University, Shanghai, China

3. Laboratory of Clinical Immunology and Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

4. Infection in Immunocompromised Pediatric Patients Research Group, Vall d’Hebron Research Institute, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

5. Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

6. Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain

7. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France

8. University of Paris, Imagine Institute, Paris, France

9. Diagnostic Immunology Group, Vall d’Hebron Research Institute, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

10. Immunology Division, Genetics Department, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain

11. Laboratory of Virology, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France

12. Pediatric Neurology Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

13. Howard Hughes Medical Institute, New York, NY

Abstract

Enterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.1641+1G>C). Their fibroblasts respond poorly to extracellular (TLR3) or intracellular (MDA5) poly(I:C) stimulation. The baseline (TLR3) and EV-responsive (MDA5) levels of IFN-β in the patients’ fibroblasts are low. EV growth is enhanced at early and late time points of infection in TLR3- and MDA5-deficient fibroblasts, respectively. Treatment with exogenous IFN-α2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-α2b rescues viral susceptibility fully only in MDA5-deficient fibroblasts. Finally, the poly(I:C) and viral phenotypes of fibroblasts are rescued by the expression of WT TLR3 or MDA5. Human TLR3 and MDA5 are critical for cell-intrinsic immunity to EV, via the control of baseline and virus-induced type I IFN production, respectively.

Funder

National Center for Advancing Translational Sciences

National Institutes of Health

Agence Nationale de la Recherche

Rockefeller University

Institut National de la Santé et de la Recherche Médicale

University of Paris

St. Giles Foundation

Division of Intramural Research, National Institute of Allergy and Infectious Diseases

Publisher

Rockefeller University Press

Subject