Author/Editor		Onorati, Marco; Li, Zhen; Liu, Fuchen; Sousa, André M.M.; Nakagawa, Naoki; Li, Mingfeng; Dell'Anno, Maria Teresa; Gulden, Forrest O.; Mlakar, Jernej; Popović, Mara
Title		Zika virus disrupts phospho-TBK1 localization and mitosis in human neuroepithelial stem cells and radial glia
Type		članek
Vol. and No.		Letnik 16, št. 10
Publication year		2016
Volume		str. 2576-2592
ISSN		2211-1247 - Cell reports
Language		eng
Abstract		The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells and their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization and cell death. ZIKV infection of NES cells and RGCs causes centrosomal depletion and mitochondrial sequestration of phospho-TBK1 during mitosis. We also found that nucleoside analogs inhibit ZIKV replication in NES cells, protecting them from ZIKV-induced pTBK1 relocalization and cell death. We established a model system of human neural stem cells to reveal cellular and molecular mechanisms underlying neurodevelopmental defects associated with ZIKV infection and its potential treatment.
Keywords		virus Zika nevroepitelijske matične celice radialna glija kompleks EJC Zika virus neuroepithelial stem cells radial glia