@article{56878caf5121440fbc5a633a3ac2d1eb,
title = "Zika virus propagation and release in human fetal astrocytes can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869",
abstract = "Zika virus (ZIKV) is a neurotrophic flavivirus that is capable of infecting humans, leading to brain abnormalities during fetal development. The ZIKV infectivity in neural target cells remains poorly understood. Here, we found that ZIKV specifically infected glial fibrillary acidic protein- and S100B-positive primary human astrocytes derived from fetal brains. In contrast, neuron-specific Class III β-tubulin (TuJ1)-positive neurons in the astrocyte cultures and SOX2-positive neural progenitor cells derived from the fetal brains were less susceptible to ZIKV infection compared with astrocytes. The infected astrocytes released competent viral particles and manifested programmed cell death with a progressive cytopathic effect. Interestingly, ZIKV infection in human fetal astrocytes induced a significant increase of extracellular vesicles (EVs). Treatment with GW4869, a specific inhibitor of neutral sphingomyelinase-2, decreased EV levels, suppressed ZIKV propagation, and reduced the release of infectious virions in astrocytes. Therefore, ZIKV infects primary human fetal astrocytes and the infection can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. Further investigation into sphingomyelin metabolism and EVs may provide insights to the therapeutic treatment of ZIKV infection.",
author = "Yunlong Huang and Yuju Li and Hainan Zhang and Runze Zhao and Ran Jing and Yinghua Xu and Miao He and Justin Peer and Kim, {Yeong C.} and Jiangtao Luo and Zenghan Tong and Jialin Zheng",
note = "Funding Information: We kindly thank Dr. Chantey Morris, Dr. Santhi Gorantla, Dr. Beiqing Wu, Dr. Kaihong Su, Dr. Yi Wang, and Ms. Li Wu for technical support; Lenal Bottoms and Dr. Matthew Mitchell for reviewing the manuscript. We thank Janice A. Taylor and James R. Talaska of the Advanced Microscopy Core Facility for providing assistance with confocal microscopy. Support for the UNMC Advanced Microscopy CORE Facility was provided by the Nebraska Research Initiative, the Fred and Pamela Buffett Cancer Center Support Grant (P30CA036727), an Institutional Development Award (IDeA) from the NIGMS of the NIH (P30GM106397), and NIH S10RR027301 for the LSM 710 Zeiss Confocal Microscope. We also would like to thank Tom Bargar and Nicholas Conoan of the Electron Microscopy Core Facility (EMCF) at the University of Nebraska Medical Center for technical assistance. The EMCF is supported by state funds from the Nebraska Research Initiative (NRI) and the University of Nebraska Foundation, and institutionally by the Office of the Vice Chancellor for Research. This work was supported by grants from National Key Basic Research Program of China (973Program Grant No. 2014CB965000, project 1 No. 2014CB965001 and project 3 No. 2014CB965003), Innovative Research Groups of the National Natural Science Foundation of China (#81221001 to J.Z.), and Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (#81329002 to J.Z.); National Institutes of Health: 2R56NS041858-15A1 (J.Z.), 1R01NS097195-01 (J.Z.), and R03 NS094071-01 (Y.H.). Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41421-018-0017-2",
language = "English (US)",
volume = "4",
journal = "Cell Discovery",
issn = "2056-5968",
publisher = "Nature Publishing Group",
number = "1",
}