In 2015, the Zika virus reached pandemic levels with Brazil reporting over 2400 cases, compared to 147 cases in 2014 . The Zika outbreak is still ongoing in 2016, primarily in the Americas. Zika is mainly spread to individuals via the bite of an infected Aedes species mosquito. If an individual is infected during pregnancy, it is thought that fetuses can develop a birth defect of the brain called microcephaly, which is an abnormal smallness of the head.
Research groups in São Paulo and San Diego sought to investigate the causal relationship between the Brazilian Zika Virus (ZIKVBR) and birth defects. Despite a number of studies being done on a Zika strain isolated in Africa (reviewed in ), which shares an 87-90% sequence similarity with the Brazilian isolates [3,4], brain abnormalities were not reported in the African isolates. As a result, evidence is lacking regarding how ZIKVBR results in brain malformations, such as microcephaly. To investigate this gap in the field, the group isolated ZIKVBR from an infected child living in Brazil and utilized three sophisticated experimental models:
A mouse model, where pregnant mice were infected with ZIKVBR and newborns were evaluated immediately after birth
Progenitor cells and stem cells are able to change and develop (differentiate) into specific types of cells. Thus, to study potential impairment in the growth and development of nervous tissue, neural stem cells and progenitor cells (NPC) were used
To study early brain development, 2 in vitro three-dimensional neural cell culture systems were utilized, including neurospheres that contain free-floating clusters of neural stem cells, and cerebral organoids, which are artificially grown miniature organs that resemble the first trimester of human neurodevelopment 
The researchers first utilized a method called quantitative PCR to quantify the amount of nucleic acid (DNA, RNA) in various tissues, and found significantly more viral ZIKVBR RNA in the brain tissue, suggesting Zika is capable of infecting nerve cells. Using the NPC model, the researchers found that ZIKVBR was capable of infecting brain progenitor cells specifically. Microscopy analysis of all models demonstrated that ZIKVBR infection resulted in a reduction in brain layer thickness and cell number (signs of microcephaly). Evidence of cellular death was also apparent, and 2 cellular pathways were found responsible: apoptosis and autophagy:
Apoptosis involves the elimination of harmful cells in the body, and can be thought of as programmed cell death
Autophagy involves the breakdown of unnecessary or dysfunctional cellular components, and can be thought of as self-eating. One can imagine autophagy as our recycling system, whereby our waste is converted into reusable objects to prevent wasting potentially useful materials
The model proposed by these research groups is that ZIKVBR is capable of causing microcephaly by targeting brain progenitor cells, as well as inducing cell death and impairing neurodevelopment. Not only do these results reinforce the link between ZIKVBR and congenital brain malformations, it also provides 3 experimental models that can be utilized for future pre-clinical studies to combat the harmful impact of ZIKVBR on the development of the human brain.
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