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Cell Rep. 2016 Sep 6;16(10):2576-92. doi: 10.1016/j.celrep.2016.08.038. Epub 2016 Aug 24.

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

Author information

1
Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
2
UNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
3
Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
4
Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
5
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE13BZ, UK.
6
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
7
Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia.
8
Department of Virology, Institut Pasteur, 75724 Paris Cedex 15, France.
9
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA.
10
Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA; Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: tamas.horvath@yale.edu.
11
Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: brett.lindenbach@yale.edu.
12
Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Departments of Genetics and Psychiatry, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: nenad.sestan@yale.edu.

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 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.

PMID:
27568284
PMCID:
PMC5135012
[Available on 2017-09-06]
DOI:
10.1016/j.celrep.2016.08.038
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