Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis.
Cells, Cultured
Child, Preschool
Encephalitis, Viral
/ genetics
Enterovirus
/ drug effects
Enterovirus Infections
/ genetics
Female
Fibroblasts
/ drug effects
Humans
Infant
Interferon alpha-2
/ pharmacology
Interferon-Induced Helicase, IFIH1
/ genetics
Interferon-beta
/ immunology
Loss of Function Mutation
Male
Metabolism, Inborn Errors
/ genetics
Poly I-C
/ pharmacology
Rhombencephalon
/ virology
Toll-Like Receptor 3
/ genetics
Virus Replication
/ drug effects
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
06 12 2021
06 12 2021
Historique:
received:
22
06
2021
revised:
31
08
2021
accepted:
11
10
2021
entrez:
2
11
2021
pubmed:
3
11
2021
medline:
28
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34726731
pii: 212742
doi: 10.1084/jem.20211349
pmc: PMC8570298
pii:
doi:
Substances chimiques
Interferon alpha-2
0
Interferon-alpha2b
0
TLR3 protein, human
0
Toll-Like Receptor 3
0
Interferon-beta
77238-31-4
IFIH1 protein, human
EC 3.6.1.-
Interferon-Induced Helicase, IFIH1
EC 3.6.4.13
Poly I-C
O84C90HH2L
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI088364
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001866
Pays : United States
Organisme : NIH HHS
ID : UL1TR001866
Pays : United States
Organisme : Intramural NIH HHS
Pays : United States
Informations de copyright
© 2021 Chen et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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