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The Brazilian Zika virus strain causes birth defects in experimental models
Open accessAbstract
Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.
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“A study using 2D iPSC-derived neural progenitor cells68 and two later studies69,70 that used both 2D neural precursor cells (NPCs) and brain organoids demonstrated this association.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [70]
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“another reported reductions in progenitor cell and neuron numbers due to apoptosis70”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [70]
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Metadata
- Authors
- Cugola, F. R., Fernandes, I. R., Russo, F. B., Freitas, B. C., Dias, J. L. M., Guimarães, K. P., Benazzato, C., Almeida, N., Pignatari, G. C., Romero, S., Polonio, C. M., Cunha, I., Freitas, C. L., Brandão, W. N., Rossato, C., Andrade, D. G., Faria, D. D. P., Garcez, A. T., Buchpigel, C. A., Braconi, C. T., Mendes, E., Sall, A. A., Zanotto, P. M. D. A., Peron, J. P. S., Muotri, A. R., & Beltrão-Braga, P. C. B.
- Affiliations
- Universidade de São Paulo (BR)
- University of California San Diego (US)
- Institut Pasteur de Dakar (SN)
- ORCID
- Cugola, Fernanda R.
- Fernandes, Isabella R.
- Russo, Fabiele B.
- Freitas, Beatriz C.
- Benazzato, Cecília
- Almeida, Nathalia
- Polonio, Carolina M.
- Freitas, Carla L.
- Brandão, Wesley N.
- Rossato, Cristiano
- Faria, Daniele de P.
- Garcez, Alexandre T.
- Braconi, Carla T.
- Sall, Amadou A.
- Zanotto, Paolo M. de A.
- Peron, Jean Pierre S.
- Muotri, Alysson R.
- Venue
- Nature
- Published
- 2016-05-11
- Volume
- 534
- Issue
- 7606
- Pages
- 267-271
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4902174
- OpenAlex
- W2356757232
- Cited by
- 1,326
- References
- 37
- Citations by year
- 2026: 31 · 2025: 57 · 2024: 70 · 2023: 73 · 2022: 102 · 2021: 147 · 2020: 132 · 2019: 147 · 2018: 196 · 2017: 246 · 2016: 124
- FWCI
- 235.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- Fundação de Amparo à Pesquisa do Estado de São Paulo (11/18703-2, 2014/, 14/17766-9)
- National Institutes of Health
- National Institute of Mental Health (U19MH107367, R01MH094753)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Keywords
- Zika virus, microcephaly, congenital brain malformation, fetal growth restriction, placental infection, cortical progenitor cells, apoptosis, autophagy, brain organoids, brain development, fetal infection, Guillain-Barré syndrome
- MeSH terms
- Zika Virus Infection, Zika Virus, Animals, Autophagy, Brain, Brazil, Disease Models, Animal, Female, Fetal Growth Retardation, Fetus, Microcephaly, Organoids, Placenta, Pregnancy, Apoptosis, Cell Proliferation, Mice, Neural Stem Cells
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