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Volume 29, No 4, Apr 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 4, April 2019: 265-273

ORIGINAL ARTICLES

Zika virus infection induces RNAi-mediated antiviral immunity in human neural progenitors and brain organoids

Yan-Peng Xu 1, Yang Qiu 2, Boya Zhang 3,4, Guilai Chen 3,4, Qi Chen 1, Miao Wang 2, Fan Mo 3,4, Jiuyue Xu 2,4, Jin Wu 5, Rong-Rong Zhang 1,6, Meng-Li Cheng 1,6, Na-Na Zhang 1, Bao Lyu 2,7, Wen-Liang Zhu 3,4, Meng-Hua Wu 3,4, Qing Ye 1, Da Zhang 3,4, Jiang-Hong Man 5, Xiao-Feng Li 1, Jie Cui 2,4, Zhiheng Xu 4,8, Baoyang Hu 3,4, Xi Zhou 2,4,7 and Cheng-Feng Qin 1,6

1 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, 100071 Beijing, China; 2State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences (CAS), Wuhan 430071 Hubei, China; 3State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, CAS, 100101 Beijing, China; 4University of Chinese Academy of Sciences, 100049 Beijing, China; 5State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 100850 Beijing, China; 6School of Basic Sciences, Anhui Medical University, Hefei 230032 Anhui, China; 7College of Life Sciences, Wuhan University, Wuhan 430072 Hubei, China and 8State Key Laboratory of Molecular Developmental Biology, Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, CAS, 100101 Beijing, China
 Correspondence: Baoyang Hu (byhu@ioz.ac.cn) or Xi Zhou (zhouxi@wh.iov.cn) or Cheng-Feng Qin (qincf@bmi.ac.cn)These authors contributed equally: Yan-Peng Xu, Yang Qiu, Boya Zhang, Guilai Chen

The re-emergence of Zika virus (ZIKV) in the Western Hemisphere has resulted in global public health crisis since 2015. ZIKV preferentially infects and targets human neural progenitor cells (hNPCs) and causes fetal microcephaly upon maternal infection. hNPCs not only play critical roles during fetal brain development, but also persist in adult brain throughout life. Yet the mechanism of innate antiviral immunity in hNPCs remains largely unknown. Here, we show that ZIKV infection triggers the abundant production of virus-derived small interfering RNAs in hNPCs, but not in the more differentiated progenies or somatic cells. Ablation of key RNAi machinery components significantly enhances ZIKV replication in hNPCs. Furthermore, enoxacin, a broad-spectrum antibiotic that is known as an RNAi enhancer, exerts potent anti-ZIKV activity in hNPCs and other RNAi-competent cells. Strikingly, enoxacin treatment completely prevents ZIKV infection and circumvents ZIKV-induced microcephalic phenotypes in brain organoid models that recapitulate human fetal brain development. Our findings highlight the physiological importance of RNAi-mediated antiviral immunity during the early stage of human brain development, uncovering a novel strategy to combat human congenital viral infections through enhancing RNAi.


https://doi.org/10.1038/s41422-019-0152-9

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