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Cell Stem Cell. 2017 Mar 2;20(3):397-406.e5. doi: 10.1016/j.stem.2016.12.005. Epub 2017 Jan 26.

Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids.

Author information

1
Center for Molecular Medicine and Institute of Biochemistry I of the University of Cologne, Cologne 50931, Germany.
2
Institute for Medical Microbiology, Immunology, and Hygiene, University of Cologne, Cologne 50935, Germany.
3
Department of Life Sciences, University of Siena, Siena 53100, Italy.
4
Department of Dermatology, University of Cologne, Cologne 50931, Germany.
5
Center for Molecular Medicine of the University of Cologne, Cologne 50931, Germany.
6
Department of Virology, Helsinki University Hospital, Helsinki 00029, Finland.
7
Department of Virology, Helsinki University Hospital, Helsinki 00029, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki 00029, Finland.
8
Bernhard Nocht Institute for Tropical Medicine, Hamburg 20359, Germany; German Center for Infection Research (DZIF), Bonn-Cologne, Cologne 50935, Germany.
9
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.
10
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.
11
Center for Molecular Medicine and Institute of Biochemistry I of the University of Cologne, Cologne 50931, Germany. Electronic address: jay.gopalakrishnan@uni-koeln.de.

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.

KEYWORDS:

3D human brain organoids; NPCs; Zika virus; centrosomes; cilia; microcephaly; neural progenitor cells; premature NPC differentiation

PMID:
28132835
DOI:
10.1016/j.stem.2016.12.005
[Indexed for MEDLINE]
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