By Siouxsie Wiles 05/03/2016


Scientists have just reported that in the lab, the Zika virus can infect and destroy neural stem cells that give rise to the brain’s cerebral cortex.

Updated 6/3/2016 to include links to new papers

Zika is the virus spread by mosquitoes (and more rarely by sexual transmission) that is currently causing concern across the Americas and Pacific because infection during pregnancy has been linked to miscarriage and babies being born with smaller heads and brains (known as microcephaly). All sort of other explanations have been put forward for the rise in microcephaly cases in Brazil, including genetically-modified mosquitoes and pesticides.

Today, scientists from the US have published a paper in the journal Cell Stem Cell in which they describe their experiments infecting neuronal stem cells with the Zika virus (1). The neuronal cells they infected were made from human induced pluripotent stem cells (iPSCs). Stem cells are cells which can be programmed to turn into different types of cells – brain cells, kidney cells, heart cells…  iPSCs are stem cells that have been made from adult cells rather than embryonic cells. What the scientists have done is taken cells from an adult human, turned them into iPSCs and then programmed those to turn into the neuronal stem cells that would form the cortex of a developing brain.

The scientists grew the Zika virus in mosquito cells for a few days and then used those viruses to infect the neuronal stem cells. They found that Zika was able to turn the neuronal stem cells into little virus factories – from a single infected cell, the virus spread to a whole plate of cells within 3 days. And it didn’t look the human cells put up a fight.

Update: Brazilian authors have just published a preprint (so its not been peer-reviewed yet) on their experiments infecting human neural stem cells growing as neurospheres and cerebral organoids with Zika virus (2). They find the same thing as the US groups, that the infected cells die.

It’s important to remember that this is an ‘in the dish’ type of experiment and not infection of a developing foetus brain but it does support the US Centers for Disease Control’s (CDC) recent findings on Zika infection in pregnant US travellers. Of the six women infected during the first trimester of their pregnancy, two women miscarried, two women elected to terminate their pregnancies and one woman gave birth to a baby with severe microcephaly. The sixth woman is still pregnant. The CDC described the case of “Patient B”, a woman in her 30s whose 20 week scan revealed a foetus with severe brain abnormalities, including the band of nerves between the two hemispheres of the brain (the corpus callosum) being missing and the brain not having as much tissue as it would normally. If Zika virus is able to infect and destroy developing brain cells then this would certainly help explain those findings.

Update: Brasil and colleagues have just published a preliminary report of their findings following a cohort of pregnant women in Rio de Janeiro (3). They enrolled 88 women between September 2015 and February 2016, 72 of whom tested positive for Zika virus. 42 of the women who tested positive and all of the women who tested negative had ultrasounds. Fetal abnormalities were seen for 12 of the 42 Zika-positive women (29%) and in none of the 16 Zika-negative women. Two foetuses died (one at 36 weeks and the other at 38 weeks) and 19 had some form of abnormality.  This is one of the saddest statements in the paper: “To date, 8 of the 42 women in whom fetal ultrasonography was performed have delivered their babies, and the ultrasonographic findings have been confirmed.” In other words, the women’s pregnancies were not terminated and they have delivered babies with the problems identified on the scans. The authors conclude: “Despite mild clinical symptoms, ZIKV infection during pregnancy appears to be associated with grave outcomes, including fetal death, placental insufficiency, fetal growth restriction, and CNS [central nervous system] injury.”

This is an important development, but there are still so many unanswered questions. Why is the infection so mild in adults? How does the virus get to the developing foetus? Why don’t the cells fight back? Answers to these questions and more are crucial to finding a vaccine or treatment.

Featured image: Death of neuronal stem cells after Zika virus infection. Zika virus is stained in green, Dying cells are stained red, cell DNA is stained grey.

References:

  1. Tang, Hammack, Ogden, Wen, and Qian et al. (2016). Zika Virus Infects Human Cortical Neural Precursors and Attenuates Their Growth. Cell Stem Cell. 
  2. Garcez PP, Loiola EC, Madeiro da Costa RF, Higa L, Trindade P, Delvecchio R, Nascimento JM, Brindeiro RM, Tanuri A, Rehen SK. (2016) Zika virus impairs growth in human neurospheres and brain organoids. PeerJ Preprints 4:e1817v2
  3. Brasil et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro — Preliminary Report. New England Journal of Medicine. DOI: 10.1056/NEJMoa1602412.