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

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

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)606-617
Number of pages12
JournalJournal of Clinical Immunology
Issue number3
Publication statusPublished - Apr 2022
Externally publishedYes


  • Encephalitis
  • Enterovirus 71
  • Inborn error of immunity
  • Toll-like receptor 3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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