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Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly

Author

Listed:
  • Zhiwei Lei

    (Jinan University
    Qingyuan People’s Hospital)

  • Yu Gu

    (Jinan University)

  • Ying Liu

    (Jinan University)

  • Hailiang Liu

    (Southern Medical University)

  • Xiaohua Lu

    (Guangzhou Medical University
    Chinese Academy of Sciences)

  • Weijie Chen

    (Jinan University)

  • Lu Zhou

    (Jinan University)

  • Pan Pan

    (The First Affiliated Hospital of Jinan University)

  • Zhuohong Chen

    (Jinan University)

  • Zhaoyang Yue

    (Jinan University)

  • Jinhui Ruan

    (Foshan Institute of Medical Microbiology)

  • Leqing Zhu

    (Bioland)

  • Guangqiang Li

    (Jinan University)

  • Xichun Xia

    (Jinan University)

  • Yang Yu

    (Guangzhou Medical University
    Chinese Academy of Sciences)

  • Jianfeng Dai

    (Soochow University)

  • Xin Chen

    (Jinan University)

Abstract

Zika virus (ZIKV) is a member of the Flaviviridae family and causes congenital microcephaly and Guillain–Barré syndrome. Currently, there is a lack of approved vaccines or therapies against ZIKV infection. In this study, we profile vRNA‒host protein interactomes at ZIKV stem‒loop B (SLB) and reveal that interleukin enhancer binding factor 3 (ILF3) and DEAH-box helicase 9 (DHX9) form positive regulators of antiviral RNA inference in undifferentiated human neuroblastoma cells and induced pluripotent stem cell-derived human neural stem cells (iPSC–NSCs). Functionally, ablation of ILF3 in brain organoids and Nestin-Cre ILF3 cKO foetal mice significantly enhance ZIKV replication and aggravated ZIKV-induced microcephalic phenotypes. Mechanistically, ILF3/DHX9 enhance DICER processing of ZIKV vRNA-derived siRNAs (vsiR-1 and vsiR-2) to exert anti-flavivirus activity. VsiR-1 strongly inhibits ZIKV NS5 polymerase activity and RNA translation. Treatment with the vsiR-1 mimic inhibits ZIKV replication in vitro and in vivo and protected mice from ZIKV-induced microcephaly. Overall, we propose a novel therapeutic strategy to combat flavivirus infection.

Suggested Citation

  • Zhiwei Lei & Yu Gu & Ying Liu & Hailiang Liu & Xiaohua Lu & Weijie Chen & Lu Zhou & Pan Pan & Zhuohong Chen & Zhaoyang Yue & Jinhui Ruan & Leqing Zhu & Guangqiang Li & Xichun Xia & Yang Yu & Jianfeng , 2025. "Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56859-x
    DOI: 10.1038/s41467-025-56859-x
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    References listed on IDEAS

    as
    1. Baoyu Zhao & Guanghui Yi & Fenglei Du & Yin-Chih Chuang & Robert C. Vaughan & Banumathi Sankaran & C. Cheng Kao & Pingwei Li, 2017. "Structure and function of the Zika virus full-length NS5 protein," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    2. Fabien Aubry & Sofie Jacobs & Maïlis Darmuzey & Sebastian Lequime & Leen Delang & Albin Fontaine & Natapong Jupatanakul & Elliott F. Miot & Stéphanie Dabo & Caroline Manet & Xavier Montagutelli & Arte, 2021. "Recent African strains of Zika virus display higher transmissibility and fetal pathogenicity than Asian strains," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Madeline A. Lancaster & Magdalena Renner & Carol-Anne Martin & Daniel Wenzel & Louise S. Bicknell & Matthew E. Hurles & Tessa Homfray & Josef M. Penninger & Andrew P. Jackson & Juergen A. Knoblich, 2013. "Cerebral organoids model human brain development and microcephaly," Nature, Nature, vol. 501(7467), pages 373-379, September.
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