Details

Autor(en) / Beteiligte

• Onorati, Marco
• Li, Zhen
• Liu, Fuchen
• Sousa, André M.M.
• Nakagawa, Naoki
• Li, Mingfeng
• Dell’Anno, Maria Teresa
• Gulden, Forrest O.
• Pochareddy, Sirisha
• Tebbenkamp, Andrew T.N.
• Han, Wenqi
• Pletikos, Mihovil
• Gao, Tianliuyun
• Zhu, Ying
• Bichsel, Candace
• Varela, Luis
• Szigeti-Buck, Klara
• Lisgo, Steven
• Zhang, Yalan
• Testen, Anze
• Gao, Xiao-Bing
• Mlakar, Jernej
• Popovic, Mara
• Flamand, Marie
• Strittmatter, Stephen M.
• Kaczmarek, Leonard K.
• Anton, E.S.
• Horvath, Tamas L.
• Lindenbach, Brett D.
• Sestan, Nenad

Titel

Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia

Ist Teil von

• Cell reports (Cambridge), 2016-09, Vol.16 (10), p.2576-2592

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 as well as 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. [Display omitted] •Derivation of human neocortical and spinal cord neuroepithelial stem (NES) cells•Zika virus (ZIKV) infects NES cells and radial glia, impairing mitosis and survival•ZIKV induces mitochondrial sequestration of centrosomal phospho-TBK1•Nucleoside analogs inhibit ZIKV replication, protecting NES cells from cell death Onorati et al. establish neuroepithelial stem (NES) cells as a model for studying human neurodevelopment and ZIKV-induced microcephaly. Together with analyses in human brain slices and microcephalic human fetal tissue, they find that ZIKV predominantly infects NES and radial glial cells, reveal a pivotal role for pTBK1, and find that nucleoside analogs inhibit ZIKV replication, protecting NES cells from cell death.