Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis
Chen, Jie (Shanghai Jiaotong University)
Jing, Huie (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Martin-Nalda, Andrea (Hospital Universitari Vall d'Hebron)
Bastard, Paul (University of Paris)
Rivière, Jacques G. (Hospital Universitari Vall d'Hebron)
Liu, Zhiyong (The Rockefeller University (New York, Estats Units d'Amèrica))
Colobrán Oriol, Roger (Hospital Universitari Vall d'Hebron)
Lee, Danyel (University of Paris)
Tung, Wesley (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Manry, Jeremy (University of Paris)
Hasek, Mary (The Rockefeller University (New York, Estats Units d'Amèrica))
Boucherit, Soraya (University of Paris)
Lorenzo, Lazaro (University of Paris)
Rozenberg, Flore (Cochin Hospital (Paris, França))
Aubart, Mélodie (Necker-Enfants Malades Hospital, (Paris, França))
Abel, Laurent (University of Paris)
Su, Helen C. (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Soler-Palacín, Pere (Hospital Universitari Vall d'Hebron)
Casanova, Jean-Laurent (Howard Hughes Medical Institute (New York, Estats Units d'Amèrica))
Zhang, Shen-Ying (University of Paris)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	The authors report inborn error of TLR3 or MDA5 in two unrelated children with enterovirus rhombencephalitis. TLR3 and MDA5 may control anti-enterovirus immunity in central nervous system cells via the maintenance of basal or virus-induced type I IFN production, respectively. 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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra, i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	The journal of experimental medicine, Vol. 218 (november 2021) , ISSN 1540-9538

DOI: 10.1084/jem.20211349
PMID: 34726731

20 p, 4.1 MB

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