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

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A Correction to this article was published on 11 April 2022

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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.

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Data Availability

All data generated or analyzed during this study are included in this published article and supplementary information.

Code Availability

Not applicable.

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Acknowledgements

We thank the patients and their families for participating in this study.

Funding

This work was supported by Chang Gung Memorial Hospital (CMRPG3F1211, CMRPD190621, and 1A0681) and the National Science Council in Taiwan (NSC-98–2320-B-182–040-MY2 and MOST 110-2327-B-006-004).

Author information

Author notes

  1. Cheng-Lung Ku, Tzou-Yien Lin, and Luan-Yin Chang contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259 Wen-Hwa 1st Road, Kwei-Shan 333, Taoyuan, Taiwan

    Chen-Yen Kuo, Cheng-Lung Ku, Chia-Chi Lo & Jing-Ya Ding

  2. Division of Infectious Diseases, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, No. 5, Fu-Shin St, Kwei-Shan 333, Taoyuan, Taiwan

    Chen-Yen Kuo & Tzou-Yien Lin

  3. College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Chen-Yen Kuo & Tzou-Yien Lin

  4. Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan

    Cheng-Lung Ku

  5. Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Cheng-Lung Ku

  6. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Hye-Kyung Lim, Jean-Laurent Casanova & Shen-Ying Zhang

  7. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, Paris, France

    Hye-Kyung Lim, Jean-Laurent Casanova & Shen-Ying Zhang

  8. Imagine Institute, Paris Descartes University, Paris, France

    Hye-Kyung Lim, Jean-Laurent Casanova & Shen-Ying Zhang

  9. Division of Pediatric Critical Care Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Shao-Hsuan Hsia & Jainn-Jim Lin

  10. Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan

    Rei-Lin Kuo

  11. Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan

    Rei-Lin Kuo

  12. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  13. Pediatric Immuno-Hematology Unit, Necker Hospital, AP-HP, Necker Hospital for Sick Children, Paris, France

    Jean-Laurent Casanova

  14. Department of Pediatrics, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan

    Luan-Yin Chang

Authors
  1. Chen-Yen Kuo
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  2. Cheng-Lung Ku
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Contributions

Cheng-Lung Ku and Shen-Ying Zhang conceived and designed the experiments; Chen-Yen Kuo, Hye-Kyung Lim, Chia-Chi Lo, and Jing-Ya Ding conducted the research; Chia-Chi Lo, Chen-Yen Kuo, and Cheng-Lung Ku analyzed data and wrote the manuscript; Chen-Yen Kuo, Shao-Hsuan Hsia, Jainn-Jim Lin, Tzou-Yien Lin, and Loan-Ying Chang provided patient samples and history; Jie Chen provided experiment help during the process of revision; Rei-Lin Kuo, Shen-Ying Zhang, and Jean-Laurent Casanova provided experiment support and expertise. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Cheng-Lung Ku, Luan-Yin Chang or Tzou-Yien Lin.

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Ethics Approval

The study was conducted with approval from the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 201100792B0).

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All patients provided written informed consent approved by the Institutional Review Board of Chang Gung Memorial Hospital. Blood samples and skin biopsy specimens were obtained from patients and their relatives, with written informed consent, in accordance with the Declaration of Helsinki.

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Not applicable.

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The authors declare no competing interests.

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Kuo, CY., Ku, CL., Lim, HK. et al. Life-Threatening Enterovirus 71 Encephalitis in Unrelated Children with Autosomal Dominant TLR3 Deficiency. J Clin Immunol 42, 606–617 (2022). https://doi.org/10.1007/s10875-021-01170-9

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