title: Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia.
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.
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Marco
authors: M
authors: Onorati
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Zhen
authors: Z
authors: Li
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Fuchen
authors: F
authors: Liu
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: André M M
authors: AMM
authors: Sousa
authors: UNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: Naoki
authors: N
authors: Nakagawa
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Mingfeng
authors: M
authors: Li
authors: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Maria Teresa
authors: MT
authors: Dell'Anno
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Forrest O
authors: FO
authors: Gulden
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Sirisha
authors: S
authors: Pochareddy
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Andrew T N
authors: ATN
authors: Tebbenkamp
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Wenqi
authors: W
authors: Han
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Mihovil
authors: M
authors: Pletikos
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Tianliuyun
authors: T
authors: Gao
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Ying
authors: Y
authors: Zhu
authors: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Candace
authors: C
authors: Bichsel
authors: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Luis
authors: L
authors: Varela
authors: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Klara
authors: K
authors: Szigeti-Buck
authors: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE13BZ, UK.
authors: Steven
authors: S
authors: Lisgo
authors: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Yalan
authors: Y
authors: Zhang
authors: UNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: Anze
authors: A
authors: Testen
authors: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Xiao-Bing
authors: XB
authors: Gao
authors: Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia.
authors: Jernej
authors: J
authors: Mlakar
authors: Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia.
authors: Mara
authors: M
authors: Popovic
authors: Department of Virology, Institut Pasteur, 75724 Paris Cedex 15, France.
authors: Marie
authors: M
authors: Flamand
authors: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
authors: Stephen M
authors: SM
authors: Strittmatter
authors: 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.
authors: Leonard K
authors: LK
authors: Kaczmarek
authors: UNC Neuroscience Center and the Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: E S
authors: ES
authors: Anton
authors: 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.
authors: Tamas L
authors: TL
authors: Horvath
authors: Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: brett.lindenbach@yale.edu.
authors: Brett D
authors: BD
authors: Lindenbach
authors: 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.
authors: Nenad
authors: N
authors: Sestan
mesh_terms: D001921:Brain / Q000196:embryology / Q000473:pathology / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D005333:Fetus / Q000821:virology; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008831:Microcephaly / Q000473:pathology / Q000821:virology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D019579:Neocortex / Q000473:pathology; D058953:Neural Stem Cells / Q000201:enzymology* / Q000276:immunology / Q000648:ultrastructure / Q000821:virology*; D046569:Neuroepithelial Cells / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure / Q000821:virology*; D009457:Neuroglia / Q000473:pathology / Q000648:ultrastructure / Q000821:virology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000821:virology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009705:Nucleosides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology / Q000648:ultrastructure; D000071243:Zika Virus Infection / Q000473:pathology / Q000821:virology; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D018696:Neuroprotective Agents; D009705:Nucleosides; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D000094963:Axl Receptor Tyrosine Kinase