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Cited by 1,326Mosquito-borne diseases and controlVirology and Viral DiseasesInfectious Encephalopathies and Encephalitis

The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.

The Brazilian Zika virus strain causes birth defects in experimental models

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Cugola, Fernanda R., Fernandes, Isabella R., Russo, Fabiele B., Freitas, Beatriz C., Dias, João L. M., Guimarães, Katia P., Benazzato, Cecília, Almeida, Nathalia, Pignatari, Graciela C., Romero, Sarah, Polonio, Carolina M., Cunha, Isabela, Freitas, Carla L., Brandão, Wesley N., Rossato, Cristiano, Andrade, David G., Faria, Daniele de P., Garcez, Alexandre T., Buchpigel, Carlos A., Braconi, Carla T., Mendes, Erica, Sall, Amadou A., Zanotto, Paolo M. de A., Peron, Jean Pierre S., Muotri, Alysson R., Beltrão-Braga, Patricia C. B.·2016·Nature
DOI 10.1038/nature18296PMC PMC4902174
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Abstract

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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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
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2016-05-11
Volume
534
Issue
7606
Pages
267-271
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature18296
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
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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