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Updated: May 25, 2025
Evaluation of Zika Virus-specific T-cell Responses in Immunoprivileged Organs of Infected Ifnar1-/- Mice
Published on: October 17, 2018
Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced
Zhiwei Lei1,2, Yu Gu1, Ying Liu1
1Guangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan University, Guangzhou, China.
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.
Insights
Researchers identified interleukin enhancer binding factor 3 (ILF3) and DEAH-box helicase 9 (DHX9) as key regulators against Zika virus (ZIKV). Their findings suggest a new therapeutic strategy targeting flavivirus infections.
Area of Science:
- Virology
- Molecular Biology
- Neuroscience
Background:
- Zika virus (ZIKV), a Flaviviridae family member, causes severe congenital defects and neurological disorders.
- Current therapeutic options and vaccines against ZIKV infection are limited, necessitating novel treatment strategies.
Purpose of the Study:
- To investigate vRNA-host protein interactions at the ZIKV stem-loop B region.
- To identify host factors regulating ZIKV replication and antiviral responses.
- To explore a novel therapeutic approach for flavivirus infections.
Main Methods:
- Profiling of vRNA-host protein interactomes in human neuroblastoma cells and iPSC-derived neural stem cells.
- Functional studies involving gene ablation in brain organoids and mouse models.
- Mechanistic investigations into RNA processing and polymerase inhibition.
Main Results:
- Interleukin enhancer binding factor 3 (ILF3) and DEAH-box helicase 9 (DHX9) were identified as positive regulators of antiviral RNA interference against ZIKV.
- Ablation of ILF3 exacerbated ZIKV replication and microcephaly in vivo.
- ILF3/DHX9 enhance DICER processing of ZIKV vRNA-derived siRNAs (vsiR-1, vsiR-2), which inhibit viral polymerase activity and RNA translation.
- A vsiR-1 mimic demonstrated efficacy in inhibiting ZIKV replication and protecting against microcephaly in vivo.
Conclusions:
- ILF3 and DHX9 play critical roles in host antiviral defense against ZIKV.
- Targeting vsiR-1 represents a promising therapeutic strategy for combating ZIKV and potentially other flavivirus infections.
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