How does Zika virus cause microcephaly?

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Abstract

Here, Wen et al. review the current knowledge and progress in understanding the impact of Zika virus exposure on mammalian brain development and discuss potential underlying mechanisms.

Abstract

The re-emergence of Zika virus (ZIKV), a mosquito-borne and sexually transmitted flavivirus circulating in >70 countries and territories, poses a significant global threat to public health due to its ability to cause severe developmental defects in the human brain, such as microcephaly. Since the World Health Organization declared the ZIKV outbreak a Public Health Emergency of International Concern, remarkable progress has been made to gain insight into cellular targets, pathogenesis, and underlying biological mechanisms of ZIKV infection. Here we review the current knowledge and progress in understanding the impact of ZIKV exposure on the mammalian brain development and discuss potential underlying mechanisms.

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Most cited references 87

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Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure.

Xuyu Qian, Ha Nam Nguyen, Mingxi Song … (2016)

Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability, and tissue heterogeneity limit their broad applications. Here, we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. Together, our brain-region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and disease and for compound testing, including potential ZIKV antiviral drugs.

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Zika virus outbreak on Yap Island, Federated States of Micronesia.

Mark Duffy, Tai-Ho Chen, W. Thane Hancock … (2009)

In 2007, physicians on Yap Island reported an outbreak of illness characterized by rash, conjunctivitis, and arthralgia. Although serum from some patients had IgM antibody against dengue virus, the illness seemed clinically distinct from previously detected dengue. Subsequent testing with the use of consensus primers detected Zika virus RNA in the serum of the patients but no dengue virus or other arboviral RNA. No previous outbreaks and only 14 cases of Zika virus disease have been previously documented. We obtained serum samples from patients and interviewed patients for information on clinical signs and symptoms. Zika virus disease was confirmed by a finding of Zika virus RNA or a specific neutralizing antibody response to Zika virus in the serum. Patients with IgM antibody against Zika virus who had a potentially cross-reactive neutralizing-antibody response were classified as having probable Zika virus disease. We conducted a household survey to estimate the proportion of Yap residents with IgM antibody against Zika virus and to identify possible mosquito vectors of Zika virus. We identified 49 confirmed and 59 probable cases of Zika virus disease. The patients resided in 9 of the 10 municipalities on Yap. Rash, fever, arthralgia, and conjunctivitis were common symptoms. No hospitalizations, hemorrhagic manifestations, or deaths due to Zika virus were reported. We estimated that 73% (95% confidence interval, 68 to 77) of Yap residents 3 years of age or older had been recently infected with Zika virus. Aedes hensilli was the predominant mosquito species identified. This outbreak of Zika virus illness in Micronesia represents transmission of Zika virus outside Africa and Asia. Although most patients had mild illness, clinicians and public health officials should be aware of the risk of further expansion of Zika virus transmission. 2009 Massachusetts Medical Society

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Zika Virus Associated with Microcephaly.

Jernej Mlakar, Miša Korva, Nataša Tul … (2016)

A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.

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Author and article information

Journal

Journal ID (nlm-ta): Genes Dev

Journal ID (iso-abbrev): Genes Dev

Journal ID (hwp): genesdev

Journal ID (pmc): genesdev

Journal ID (publisher-id): GAD

Title: Genes & Development

Publisher: Cold Spring Harbor Laboratory Press

ISSN (Print): 0890-9369

ISSN (Electronic): 1549-5477

Publication date (Print): 1 May 2017

Volume: 31

Issue: 9

Pages: 849-861

Affiliations

[1 ]Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA;

[2 ]Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA;

[3 ]Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA;

[4 ]Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

[5 ]Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

[6 ]The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

[7 ]Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

[8 ]Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Author notes

Corresponding author: gming@ 123456mail.med.upenn.edu

Article

Medline ID: 8711660

DOI: 10.1101/gad.298216.117

PMC ID: 5458753

PubMed ID: 28566536

SO-VID: 1bec7e6f-a1d0-4a47-a94a-35b5e0d7cbbb

License:

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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Page count

Pages: 13

Funding

Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;

Award ID: R01MH105128

Award ID: R21MH110160

Award ID: R35NS097370

Award ID: U19AI131130

Award ID: R37NS047344

Award ID: U19MH106434

Award ID: P01NS097206

Award ID: R21HD086820

Funded by: Maryland Stem Cell Research Fund

Funded by: Foundation for Prader-Willi Research , open-funder-registry 10.13039/100002889;

Funded by: Emory University , open-funder-registry 10.13039/100006939;

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How does Zika virus cause microcephaly?

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Zika Virus

Most cited references 87

Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure.

Zika virus outbreak on Yap Island, Federated States of Micronesia.

Zika Virus Associated with Microcephaly.

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