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Development. 2016 Nov 15;143(22):4127-4136. Epub 2016 Oct 11.

Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage.

Author information

1
Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
2
University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Miami, FL 33136, USA.
3
Department of Infectious Diseases and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602, USA.
4
Department of Infectious Diseases, Department of Population Health and Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA.
5
Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA chen2014@uga.edu.

Abstract

Zika virus (ZIKV) infection of pregnant women can result in fetal brain abnormalities. It has been established that ZIKV disrupts neural progenitor cells (NPCs) and leads to embryonic microcephaly. However, the fate of other cell types in the developing brain and their contributions to ZIKV-associated brain abnormalities remain largely unknown. Using intracerebral inoculation of embryonic mouse brains, we found that ZIKV infection leads to postnatal growth restriction including microcephaly. In addition to cell cycle arrest and apoptosis of NPCs, ZIKV infection causes massive neuronal death and axonal rarefaction, which phenocopy fetal brain abnormalities in humans. Importantly, ZIKV infection leads to abnormal vascular density and diameter in the developing brain, resulting in a leaky blood-brain barrier (BBB). Massive neuronal death and BBB leakage indicate brain damage, which is further supported by extensive microglial activation and astrogliosis in virally infected brains. Global gene analyses reveal dysregulation of genes associated with immune responses in virus-infected brains. Thus, our data suggest that ZIKV triggers a strong immune response and disrupts neurovascular development, resulting in postnatal microcephaly with extensive brain damage.

KEYWORDS:

Astrogliosis; Blood–brain barrier (BBB); Microcephaly; Microglial activation; ZIKV

PMID:
27729407
PMCID:
PMC5117220
DOI:
10.1242/dev.143768
[Indexed for MEDLINE]
Free PMC Article

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