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

被引：23

作者：

Chen, Jie ^{[1
,2
]}

Jing, Huie ^{[3
]}

Martin-Nalda, Andrea ^{[4
,5
,6
]}

Bastard, Paul ^{[1
,7
,8
]}

Riviere, Jacques G. ^{[4
,5
,6
]}

Liu, Zhiyong ^{[1
]}

Colobran, Roger ^{[6
,9
,10
]}

Lee, Danyel ^{[1
,7
,8
]}

Tung, Wesley ^{[3
]}

Manry, Jeremy ^{[7
,8
]}

Hasek, Mary ^{[1
]}

Boucherit, Soraya ^{[7
,8
]}

Lorenzo, Lazaro ^{[7
,8
]}

Rozenberg, Flore ^{[11
]}

Aubart, Melodie ^{[7
,8
,12
]}

Abel, Laurent ^{[1
,7
,8
]}

Su, Helen C. ^{[3
]}

Palacin, Pere Soler ^{[4
,5
,6
]}

Casanova, Jean-Laurent ^{[1
,7
,8
,13
]}

Zhang, Shen-Ying ^{[1
,7
,8
]}

机构：

[1] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA

[2] Shanghai Jiao Tong Univ, Shanghai Hosp 6, Dept Infect Dis, Shanghai, Peoples R China

[3] NIAID, Lab Clin Immunol & Microbiol, Intramural Res Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[4] Vall dHebron Univ Hosp, Vall dHebron Res Inst, Infect Immunocompromised Pediat Patients Res Grp, Vall dHebron Barcelona Hosp Campus, Barcelona, Spain

[5] Vall dHebron Univ Hosp, Pediat Infect Dis & Immunodeficiencies Unit, Vall dHebron Barcelona Hosp Campus, Barcelona, Spain

[6] Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain

[7] Inst Natl Sante & Rech Med U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France

[8] Univ Paris, Imagine Inst, Paris, France

[9] Vall dHebron Univ Hosp, Vall dHebron Res Inst, Diagnost Immunol Grp, Vall dHebron Barcelona Hosp Campus, Barcelona, Spain

[10] Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Genet Dept, Immunol Div, Vall dHebron Barcelona Hosp Campus, Barcelona, Spain

[11] Cochin Hosp, AP HP, Lab Virol, Paris, France

[12] Necker Enfants Malad Hosp, AP HP, Pediat Neurol Dept, Paris, France

[13] Howard Hughes Med Inst, New York, NY 10065 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2021年 / 218卷 / 12期

基金：

美国国家卫生研究院;

关键词：

TOLL-LIKE RECEPTOR-3; HERPES-SIMPLEX ENCEPHALITIS; DOUBLE-STRANDED-RNA; CENTRAL-NERVOUS-SYSTEM; X-LINKED AGAMMAGLOBULINEMIA; MOUTH-DISEASE; RESPIRATORY-INFECTIONS; VIRUS ENCEPHALITIS; UNITED-STATES; ECHO VIRUS;

D O I：

10.1084/jem.20211349

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-beta 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-alpha 2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-alpha 2b 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.

引用

页数：20

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