biostudies-literatureChen JNational Center for Advancing Translational SciencesAgence Nationale de la RechercheInstitut National de la Santé et de la Recherche MédicaleNational Institutes of HealthRockefeller UniversitySt. Giles FoundationDivision of Intramural Research, National Institute of Allergy and Infectious DiseasesUniversity of Parise20211349https://www.ebi.ac.uk/biostudies/studies/S-EPMC8570298biostudies-literatureUnknown218(12)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.The Journal of experimental medicineInborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis.PMC8570298ANR-20-CE93-003ANR-18-CE15-0020-02UL1TR001866ANR-19-CE15-0009-01ANR-10-IAHU-01Jing HBastard PManry JLorenzo LChen JMartin-Nalda AHasek MTung WAbel LCasanova JLLee DAubart MZhang SYRiviere JGLiu ZColobran RBoucherit SRozenberg FSu HCSoler Palacin PfalseInborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis.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.2021-01-01T00:00:00Z2021 Dec2025-04-21T23:38:52.963Z2025-02-18T23:32:12.946ZS-EPMC85702983472673110.1084/jem.20211349