The Brazilian Zika Virus Strain Causes Birth Defects in Experimental Models

Nature. 2016 Jun 9;534(7606):267-71. doi: 10.1038/nature18296. Epub 2016 May 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Autophagy
  • Brain / pathology
  • Brain / virology
  • Brazil / epidemiology
  • Cell Proliferation
  • Disease Models, Animal*
  • Female
  • Fetal Growth Retardation / pathology
  • Fetal Growth Retardation / virology
  • Fetus / virology
  • Mice
  • Microcephaly / epidemiology
  • Microcephaly / etiology
  • Microcephaly / pathology
  • Microcephaly / virology*
  • Neural Stem Cells / pathology
  • Neural Stem Cells / virology
  • Organoids / pathology
  • Organoids / virology
  • Placenta / virology
  • Pregnancy
  • Zika Virus / pathogenicity*
  • Zika Virus Infection / complications
  • Zika Virus Infection / epidemiology
  • Zika Virus Infection / pathology
  • Zika Virus Infection / virology