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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月26日

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  • 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 Dai,
  • Xin Chen

摘要

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.