New research provides mechanism and evidence of how Zika virus causes microcephaly in newborns.


Brazil is in the midst of an unprecedented epidemic of Zika virus (ZIKV), a flavivirus that is transmitted by mosquitoes and sexually, which was first detected in the country in May 2015. Since then, reports of microcephaly in the country have increased significantly, however, a link between the virus and the birth defect has not been proven.  Now, a study from researchers at D’Or Institute for Research and Education shows that Zika virus preferentially kills developing brain cells. The team state that their results provide evidence for how Zika virus may cause brain defects in babies and specifically microcephaly, a rare birth defect in which the brain fails to grow properly.  The opensource study is published in the journal Science.

Previous studies show that microcephaly is associated with decreased neuronal production as a consequence of proliferative defects and death of cortical progenitor cells. During pregnancy, the primary etiology of microcephaly varies from genetic mutations to external insults.  The increase in the rate of microcephaly in Brazil has been associated with the recent outbreak of ZIKV. So far, ZIKV has been described in the placenta and amniotic fluid of microcephalic fetuses, and in the blood of microcephalic newborns. ZIKV had also been detected within the brain of a microcephalic fetus, and recently, there is direct evidence that ZIKV is able to infect and cause death of neural stem cells.  The current study investigates the effects of ZIKV infection in human neural stem cells growing as neural stem cells (called neurospheres) and brain organoids (mini-brains).

The current study investigated the effects of Zika virus infection in human neural stem cells derived from induced pluripotent stem cells, and growing as either clusters of neurospheres or as brain organoids; both systems represent models with which to study embryonic brain development in vitro. Results show that when the growing cells were infected with Zika virus isolated from a Brazilian patient, the virus killed most of the neurospheres within a few days; under control conditions, meanwhile, hundreds of neurospheres grew.

Data findings in a second experiment focusing on the brain organoid model show that infection with the virus reduced the growth of infected organoids by 40% compared to brain organoids under control conditions. Finally, an experiment evaluating the impact of dengue virus, a flavivirus with similarities to ZIKV, showed a significant difference in cell viability after six days, with dengue-infected cells surviving much better. The lab note that brain organoids exposed to dengue virus showed no reduction in growth compared to controls.

The team surmise that their findings suggest that the negative consequences of ZIKV in human neural stem cells are not a general feature of the flavivirus family, providing insights into ZIKV’s possible effects on the developing brain. For the future, the researchers state that other studies are necessary to further characterize the consequences of ZIKV infection during different stages of fetal development.

Source: D’Or Institute for Research and Education

 

Electron microscopy of Zika virus (orange) bound to cell membrane (brown) in neurosphere generated from human iPS cells. This material relates to a paper that appeared in the 14 April, online issue of Science, published by AAAS. The paper, by P.P. Garcez at D'Or Institute for Research and Education (IDOR) in Rio de Janeiro, Brazil, and colleagues was titled, "Zika virus impairs growth in human neurospheres and brain organoids.  Credit: Rodrigo Madeiro, PhD - IDOR.

Electron microscopy of Zika virus (orange) bound to cell membrane (brown) in neurosphere generated from human iPS cells. This material relates to a paper that appeared in the 14 April, online issue of Science, published by AAAS. The paper, by P.P. Garcez at D’Or Institute for Research and Education (IDOR) in Rio de Janeiro, Brazil, and colleagues was titled, “Zika virus impairs growth in human neurospheres and brain organoids. Credit: Rodrigo Madeiro, PhD – IDOR.

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