title: Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids.
abstract: The recent Zika virus (ZIKV) epidemic is associated with microcephaly in newborns. Although the connection between ZIKV and neurodevelopmental defects is widely recognized, the underlying mechanisms are poorly understood. Here we show that two recently isolated strains of ZIKV, an American strain from an infected fetal brain (FB-GWUH-2016) and a closely-related Asian strain (H/PF/2013), productively infect human iPSC-derived brain organoids. Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors. The main phenotypic effect was premature differentiation of neural progenitors associated with centrosome perturbation, even during early stages of infection, leading to progenitor depletion, disruption of the VZ, impaired neurogenesis, and cortical thinning. The infection pattern and cellular outcome differ from those seen with the extensively passaged ZIKV strain MR766. The structural changes we see after infection with these more recently isolated viral strains closely resemble those seen in ZIKV-associated microcephaly.
authors.affiliation: Center for Molecular Medicine and Institute of Biochemistry I of the University of Cologne, Cologne 50931, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Gabriel
authors.affiliation: Center for Molecular Medicine and Institute of Biochemistry I of the University of Cologne, Cologne 50931, Germany.
authors.forename: Anand
authors.initials: A
authors.lastname: Ramani
authors.affiliation: Institute for Medical Microbiology, Immunology, and Hygiene, University of Cologne, Cologne 50935, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Karow
authors.affiliation: Department of Life Sciences, University of Siena, Siena 53100, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardo
authors.affiliation: Center for Molecular Medicine and Institute of Biochemistry I of the University of Cologne, Cologne 50931, Germany.
authors.forename: Karthick
authors.initials: K
authors.lastname: Natarajan
authors.affiliation: Center for Molecular Medicine and Institute of Biochemistry I of the University of Cologne, Cologne 50931, Germany.
authors.forename: Li Ming
authors.initials: LM
authors.lastname: Gooi
authors.affiliation: Center for Molecular Medicine and Institute of Biochemistry I of the University of Cologne, Cologne 50931, Germany.
authors.forename: Gladiola
authors.initials: G
authors.lastname: Goranci-Buzhala
authors.affiliation: Institute for Medical Microbiology, Immunology, and Hygiene, University of Cologne, Cologne 50935, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Krut
authors.affiliation: Department of Dermatology, University of Cologne, Cologne 50931, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Peters
authors.affiliation: Center for Molecular Medicine of the University of Cologne, Cologne 50931, Germany.
authors.forename: Milos
authors.initials: M
authors.lastname: Nikolic
authors.affiliation: Department of Virology, Helsinki University Hospital, Helsinki 00029, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Kuivanen
authors.affiliation: Department of Virology, Helsinki University Hospital, Helsinki 00029, Finland.
authors.forename: Essi
authors.initials: E
authors.lastname: Korhonen
authors.affiliation: Department of Virology, Helsinki University Hospital, Helsinki 00029, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Smura
authors.affiliation: Department of Virology, Helsinki University Hospital, Helsinki 00029, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki 00029, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Vapalahti
authors.affiliation: Center for Molecular Medicine of the University of Cologne, Cologne 50931, Germany.
authors.forename: Argyris
authors.initials: A
authors.lastname: Papantonis
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Hamburg 20359, Germany; German Center for Infection Research (DZIF), Bonn-Cologne, Cologne 50935, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Schmidt-Chanasit
authors.affiliation: Department of Life Sciences, University of Siena, Siena 53100, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Riparbelli
authors.affiliation: Department of Life Sciences, University of Siena, Siena 53100, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Callaini
authors.affiliation: Institute for Medical Microbiology, Immunology, and Hygiene, University of Cologne, Cologne 50935, Germany; Center for Molecular Medicine of the University of Cologne, Cologne 50931, Germany; German Center for Infection Research (DZIF), Bonn-Cologne, Cologne 50935, Germany; CECAD, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.affiliation: Institute for Medical Microbiology, Immunology, and Hygiene, University of Cologne, Cologne 50935, Germany; Center for Molecular Medicine of the University of Cologne, Cologne 50931, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.affiliation: Center for Molecular Medicine and Institute of Biochemistry I of the University of Cologne, Cologne 50931, Germany. Electronic address: jay.gopalakrishnan@uni-koeln.de.
authors.forename: Jay
authors.initials: J
authors.lastname: Gopalakrishnan
mesh_terms: D001921:Brain / Q000473:pathology*; D002454:Cell Differentiation; D018385:Centrosome / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008938:Mitosis; D058953:Neural Stem Cells / Q000473:pathology* / Q000648:ultrastructure / Q000821:virology*; D009940:Organoids / Q000473:pathology*; D000071244:Zika Virus / Q000302:isolation & purification* / Q000502:physiology* / Q000648:ultrastructure
keywords: 3D human brain organoids; NPCs; Zika virus; centrosomes; cilia; microcephaly; neural progenitor cells; premature NPC differentiation