Life-Threatening Enterovirus 71 Encephalitis in Unrelated Children with Autosomal Dominant TLR3 Deficiency.

Abstract

PURPOSE:

Enterovirus A71 (EV71) causes a broad spectrum of childhood diseases, ranging from asymptomatic infection or self-limited hand-foot-and-mouth disease (HFMD) to life-threatening encephalitis. The molecular mechanisms underlying these different clinical presentations remain unknown. We hypothesized that EV71 encephalitis in children might reflect an intrinsic host single-gene defect of antiviral immunity. We searched for mutations in the toll-like receptor 3 (TLR3) gene. Such mutations have already been identified in children with herpes simplex virus encephalitis (HSE).

METHODS:

We sequenced TLR3 and assessed the impact of the mutations identified. We tested dermal fibroblasts from a patient with EV71 encephalitis and a TLR3 mutation and other patients with known genetic defects of TLR3 or related genes, assessing the response of these cells to TLR3 agonist poly(I:C) stimulation and EV71 infection.

RESULTS:

Three children with EV71 encephalitis were heterozygous for rare mutations-TLR3 W769X, E211K, and R867Q-all of which were shown to affect TLR3 function. Furthermore, fibroblasts from the patient heterozygous for the W769X mutation displayed an impaired, but not abolished, response to poly(I:C). We found that TLR3-deficient and TLR3-heterozygous W769X fibroblasts were highly susceptible to EV71 infection.

CONCLUSIONS:

Autosomal dominant TLR3 deficiency may underlie severe EV71 infection with encephalitis. Human TLR3 immunity is essential to protect the central nervous system against HSV-1 and EV71. Children with severe EV71 infections, such as encephalitis in particular, should be tested for inborn errors of TLR3 immunity.

• Authors: Chen-Yen Kuo, Cheng-Lung Ku, Hye-Kyung Lim, Shao-Hsuan Hsia, Jainn-Jim Lin, Chia-Chi Lo, Jing-Ya Ding, Rei-Lin Kuo, Jean-Laurent Casanova, Shen-Ying Zhang, Luan-Yin Chang, Tzou-Yien Lin
• Journal: Journal of clinical immunology (J Clin Immunol) Vol. 42 Issue 3 Pg. 606-617 (04 2022) ISSN: 1573-2592 [Electronic] Netherlands
• PMID: 35040013 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• TLR3 protein, human
• Toll-Like Receptor 3
• Poly I-C

Topics

• Cells, Cultured
• Child
• Encephalitis, Herpes Simplex (diagnosis, genetics)
• Encephalitis, Viral (diagnosis, genetics)
• Enterovirus
• Enterovirus A, Human (genetics)
• Enterovirus Infections (diagnosis, genetics)
• Humans
• Poly I-C
• Toll-Like Receptor 3 (genetics)