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

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 () and Xin Chen ()
Additional contact information
Zhiwei Lei: Jinan University
Yu Gu: Jinan University
Ying Liu: Jinan University
Hailiang Liu: Southern Medical University
Xiaohua Lu: Guangzhou Medical University
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
Jianfeng Dai: Soochow University
Xin Chen: Jinan University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56859-x

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