TY - JOUR
T1 - Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis
AU - Chen, Jie
AU - Jing, Huie
AU - Martin-Nalda, Andrea
AU - Bastard, Paul
AU - Rivière, Jacques G.
AU - Liu, Zhiyong
AU - Colobrán Oriol, Roger
AU - Lee, Danyel
AU - Tung, Wesley
AU - Manry, Jeremy
AU - Hasek, Mary
AU - Boucherit, Soraya
AU - Lorenzo, Lazaro
AU - Rozenberg, Flore
AU - Aubart, Mélodie
AU - Abel, Laurent
AU - Su, Helen C.
AU - Soler-Palacín, Pere
AU - Casanova, Jean-Laurent
AU - Zhang, Shen-Ying
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1084/jem.20211349
DO - 10.1084/jem.20211349
M3 - Article
C2 - 34726731
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
ER -