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2 results on '"MESH: Brain/virology"'

1. A clinical and histopathological study of malformations observed in fetuses infected by the Zika virus

Author

Marc Thiry, Christian Alfano, Férechté Encha-Razavi, Marine Driessen, Tania Attié-Bitach, Michel Vekemans, Marianne Leruez-Ville, Laurent Nguyen, Yves Ville, Thérèse Couderc, Marc Lecuit, Aurélie Beaufrère, Nicolas Thelen, Maryse Bonnière, Bettina Bessières, Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Gynécologie Obstétrique [CHU Necker], GIGA-Neurosciences [Université Liège], GIGA [Université Liège], Université de Liège-Université de Liège, Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This project was funded in part by the European Union's Horizon 2020 Research and Innovation Program under ZIKAlliance Grant Agreement N° 734548 (to L.N. and M.L.) and by the LabEx IBEID, Institut Pasteur, and INSERM., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 734548,ZIKAlliance(2016), DIAKITE, andrée, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, A global alliance for Zika virus control and prevention - ZIKAlliance - 2016-10-01 - 2019-09-30 - 734548 - VALID, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP]

Subjects
0301 basic medicine, Microcephaly, Pathology, [SDV]Life Sciences [q-bio], MESH: Brain/virology, Zika virus, MESH: Pregnancy, 0302 clinical medicine, Pregnancy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, microcephaly, Research Articles, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Zika Virus Infection, General Neuroscience, MESH: Aborted Fetus/physiopathology, Brain, meningoencephalitis, Meningoencephalitis, 3. Good health, Micrencephaly, [SDV] Life Sciences [q-bio], fetus, MESH: Brain/pathology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Aborted Fetus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, ER stress, Meningitis, Brazil, Hydrocephalus, medicine.medical_specialty, MESH: Hydrocephalus/pathology, MESH: Microcephaly, Pathology and Forensic Medicine, ZIKV infection, 03 medical and health sciences, MESH: Zika Virus Infection/pathology, medicine, Humans, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Fetus, MESH: Humans, business.industry, MESH: Fetus, Zika Virus, MESH: Zika Virus/pathogenicity, medicine.disease, biology.organism_classification, 030104 developmental biology, Neurology (clinical), MESH: Brazil, business, MESH: Female, micrencephaly, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

International audience; Background: The recent outbreak of Zika virus (ZIKV) infection and the associated increased prevalence of microcephaly in Brazil underline the impact of viral infections on embryo-fetal development. The aim of the present study is to provide a detailed clinical and histopathological study of the fetal disruption caused by the ZIKV, with a special focus on the associated neuropathological findings. Methods: A detailed feto-placental examination, as well as neuropathological and neurobiological studies were performed on three fetuses collected after pregnancy termination between 22 and 25 weeks of gestation (WG), because brain malforma-tions associated with a maternal and fetal ZIKV infection was diagnosed. Results: In all three cases, the maternal infection occurred during the first trimester of pregnancy. A small head was observed on the ultrasound examination of the second trimester of pregnancy and led to the diagnosis of ZIKV fetopathy and pregnancy termination. The fetal histopathological examination was unremarkable on the viscera but showed on the testis an interstitial lymphocytic infiltrate. The placenta contained a Hofbauer cells hyperplasia with signs of inflammation. Neu-ropathological findings included a meningoencephalitis and an ex vacuo hydrocepha-lus. Immunohistochemical studies showed the presence of T lymphocytic and histiocytic meningitis associated with an abundant cerebral astroglial and macrophagic reaction. In situ hybridization demonstrated, abundant ZIKV particles within the cerebral parenchyma mainly in the ventricular/subventricular zone and in the cortical plate. In addition massive cells death and endoplasmic reticulum damage were present. Conclusion: The present study reports on the clinical and histopathological findings observed in three fetuses infected by the ZIKV. It emphasizes the severity of brain damages and the minimal visceral and placental changes observed upon ZIKV infection. This confirms the selective neurotropism of ZIKV. Finally, it allows us to describe the cascade of multifactorial developmental defects leading to microcephaly.

Published
2018

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

Author

Tamas L. Horvath, Maria Teresa Dell’Anno, Xiao-Bing Gao, Naoki Nakagawa, Anze Testen, Yalan Zhang, Tianliuyun Gao, Mihovil Pletikos, Candace Bichsel, Nenad Sestan, Mingfeng Li, Sirisha Pochareddy, Brett D. Lindenbach, Leonard K. Kaczmarek, Zhen Li, Wenqi Han, Forrest O. Gulden, Fuchen Liu, André M. M. Sousa, Stephen M. Strittmatter, Andrew T.N. Tebbenkamp, Marco Onorati, Steven Lisgo, Jernej Mlakar, Marie Flamand, Mara Popović, Eva S. Anton, Luis Varela, Klara Szigeti-Buck, Ying Zhu, Department of Neuroscience [New Haven], Yale University School of Medicine-Kavli Institute for Neuroscience [New Haven], Department of Cell Biology and Physiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience [New Haven], Yale University School of Medicine, Section of Comparative Medicine [New Haven], Institute of Genetic Medicine, Newcastle University [Newcastle], Departments of pharmacology and molecular biophysics and biochemistry [New Haven], University of Ljubljana, Département de Virologie - Department of Virology, Institut Pasteur [Paris], Departments of Internal Medicine, Cellular & Molecular Physiology, Departments of Medicine and Cell Biology & Physiology, Department of Microbial Pathogenesis, Reproductive Neuroscience Unit, Department of Obstetrics and Gynecology and Department of Neurobiology, Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, Kavli Institute for Neuroscience [New Haven], Departments of Psychiatry and Genetics, This work was supported by grants NS076503, MH103339, MH105972, MH106934, MH060929, NS080388, AG034924, AG047270, DC01919, AI120113, and AI089826 from the NIH, SFARI 307705 from the Simons Foundation, and 15-RMA-YALE-31 from Connecticut Innovations’ Regenerative Medicine Research Fund. The Laboratory of Developmental Biology at the University of Washington, Seattle, and Human Developmental Biology Resource were supported by NIH award number HD0008836 and the Joint MRC/Wellcome Trust grant 099175/Z/12/Z, respectively. Additional support was provided by the Kavli Foundation and the Falk Medical Research Trust., Department of Neuroscience, Yale University School of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP), Kavli Institute for Neuroscience, Yale School of Medicine, and Yale School of Medicine [New Haven, Connecticut] (YSM)-Yale School of Medicine [New Haven, Connecticut] (YSM)

Subjects
Genetics and Molecular Biology (all), Microcephaly, Transcription, Genetic, Neocortex, MESH: Neuroepithelial Cells/ultrastructure, Biochemistry, environment and public health, MESH: Brain/virology, Neural Stem Cells, MESH: Centrosome/drug effects, MESH: Mitochondria/metabolism, lcsh:QH301-705.5, Neurons, MESH: Protein-Serine-Threonine Kinases/metabolism, Zika Virus Infection, Brain, MESH: Neurons/virology, MESH: Neural Stem Cells/virology, MESH: Neural Stem Cells/immunology, Nucleosides, MESH: Zika Virus/physiology, MESH: Virus Replication/drug effects, Neural stem cell, 3. Good health, Cell biology, Neuroepithelial cell, MESH: Brain/pathology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Spinal Cord, MESH: Neocortex/pathology, MESH: Neuroepithelial Cells/immunology, Neuroglia, MESH: Receptor Protein-Tyrosine Kinases/metabolism, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Protein Kinase Inhibitors/pharmacology, 03 medical and health sciences, MESH: Gene Expression Profiling, Fetus, Humans, MESH: Phosphorylation/drug effects, Mitosis, MESH: Neural Stem Cells/ultrastructure, Biochemistry, Genetics and Molecular Biology (all), MESH: Humans, Receptor Protein-Tyrosine Kinases, MESH: Zika Virus/pathogenicity, medicine.disease, Immunity, Innate, MESH: Mitosis/drug effects, 030104 developmental biology, MESH: Neuroprotective Agents/pharmacology, MESH: Mitochondria/drug effects, MESH: Spinal Cord/pathology, MESH: Neuroglia/ultrastructure, 0301 basic medicine, MESH: Fetus/virology, viruses, [SDV]Life Sciences [q-bio], Neuroepithelial Cells, MESH: Zika Virus/ultrastructure, Virus Replication, MESH: Neurons/drug effects, MESH: Neuroepithelial Cells/drug effects, MESH: Zika Virus Infection/pathology, MESH: Neurons/pathology, MESH: Immunity, Innate/drug effects, Phosphorylation, Genetics, Cell Death, MESH: Transcription, Genetic/drug effects, MESH: Neuroglia/virology, MESH: Nucleosides/pharmacology, Mitochondria, Neuroprotective Agents, MESH: Neuroglia/pathology, lipids (amino acids, peptides, and proteins), MESH: Zika Virus Infection/virology, Stem cell, Programmed cell death, MESH: Centrosome/metabolism, MESH: Brain/embryology, Protein Serine-Threonine Kinases, Biology, Proto-Oncogene Proteins, MESH: Microcephaly/pathology, medicine, MESH: Zika Virus/drug effects, Protein Kinase Inhibitors, Centrosome, MESH: Neural Stem Cells/enzymology, Gene Expression Profiling, MESH: Proto-Oncogene Proteins/metabolism, Zika Virus, Axl Receptor Tyrosine Kinase, MESH: Microcephaly/virology, Gene expression profiling, MESH: Cell Death/drug effects, lcsh:Biology (General), MESH: Neuroepithelial Cells/virology
Abstract

SummaryThe 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.

Published
2016

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