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Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):12273-12278. doi: 10.1073/pnas.1714624114. Epub 2017 Oct 31.

Replication of early and recent Zika virus isolates throughout mouse brain development.

Author information

1
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032; abr22@cumc.columbia.edu.
2
Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032.
3
Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032.

Abstract

Fetal infection with Zika virus (ZIKV) can lead to congenital Zika virus syndrome (cZVS), which includes cortical malformations and microcephaly. The aspects of cortical development that are affected during virus infection are unknown. Using organotypic brain slice cultures generated from embryonic mice of various ages, sites of ZIKV replication including the neocortical proliferative zone and radial columns, as well as the developing midbrain, were identified. The infected radial units are surrounded by uninfected cells undergoing apoptosis, suggesting that programmed cell death may limit viral dissemination in the brain and may constrain virus-associated injury. Therefore, a critical aspect of ZIKV-induced neuropathology may be defined by death of uninfected cells. All ZIKV isolates assayed replicated efficiently in early and midgestation cultures, and two isolates examined replicated in late-gestation tissue. Alteration of neocortical cytoarchitecture, such as disruption of the highly elongated basal processes of the radial glial progenitor cells and impairment of postmitotic neuronal migration, were also observed. These data suggest that all lineages of ZIKV tested are neurotropic, and that ZIKV infection interferes with multiple aspects of neurodevelopment that contribute to the complexity of cZVS.

KEYWORDS:

Zika virus; cortical malformations; flavivirus; microcephaly; neurotropism

PMID:
29087938
PMCID:
PMC5699088
DOI:
10.1073/pnas.1714624114
[Indexed for MEDLINE]
Free PMC Article

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