Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly
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.
Authors
- Yu Jeffrey Gu (ORCID: https://orcid.org/0000-0002-9340-9459)
- Zhiwei Lei (ORCID: https://orcid.org/0000-0002-9406-2127)
- Yang Yu (ORCID: https://orcid.org/0000-0003-0536-2783)
- Leqing Zhu (ORCID: https://orcid.org/0000-0002-4449-0318)
- Lu Zhou
- Xichun Xia (ORCID: https://orcid.org/0000-0002-5608-4499)
- Hailiang Liu (ORCID: https://orcid.org/0000-0002-4364-2826)
- Jianfeng Dai (ORCID: https://orcid.org/0000-0002-1871-8390)
- Zhaoyang Yue
- Z Chen
- Ying Liu (ORCID: https://orcid.org/0000-0002-6081-4773)
- Pan Pan (ORCID: https://orcid.org/0000-0002-7214-1393)
- Weijie Chen (ORCID: https://orcid.org/0000-0002-5356-7575)
- Xiaohua Lu (ORCID: https://orcid.org/0000-0002-6656-5069)
- Guangqiang Li (ORCID: https://orcid.org/0000-0002-4471-7439)
- Jinhui Ruan
- Xin Chen (ORCID: https://orcid.org/0000-0002-3066-2174)
Institutions
- Jinan University (CN)
- Chinese Academy of Sciences (CN)
- Soochow University (CN)
- Zhuhai People's Hospital (CN)
- Guangzhou Women and Children Medical Center (CN)
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN)
- Institute of Biophysics (CN)
- National Institute for Viral Disease Control and Prevention (CN)
- First Affiliated Hospital of Jinan University (CN)
- Southern Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1038/s41467-025-56859-x
- Citations
- 1
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 1.88
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province