Tariq Rana, Professor of Pediatrics, University of California, San Diego, and his colleagues have used human embryonic stem cells to make neural stem cells that form spherical, neural organoids that can be infected with Zika virus. By using this elegant experimental system, Rana and his coworkers discovered how Zika virus causes brain abnormalities in babies unfortunate enough to be infected by the virus while there are in their mother’s wombs.
Zika virus is a member of the “flavivirus” group of viruses. Because this virus was first recognized in the Zika forest of Uganda, the name of this forest was applied to the virus. Zika virus causes a disease that is spread by mosquitoes. The most common symptoms of Zika virus disease are a mild fever, skin rashes, muscle and joint pain, and pink eye (conjunctivitis). These symptoms normally last for 2-7 days, but the disease is self-limiting in the vast majority of cases. The more severe cases occur if the patient is a pregnant woman. The virus caused a significant outbreak in Brazil in 2015, and many pregnant women who had been infected with Zika virus gave birth to babies with abnormally small heads, a condition known as “microcephaly.”
Work with laboratory animals has established that the Zika virus-induced microcephaly is due to a smaller brain that contains fewer neurons. How does Zika virus do this?
Dr Rana and his group seem to have made a major contribution to understanding the pathology of Zika virus on unborn babies. In a paper published in the journal Cell Stem Cell, Rana and his fellow researchers report that the neural organoids made in the Rana lab from embryonic stem cell-derived neural stem cells recapitulate fetal brain development to a large extent. While these organoids are limited in what they can model, they divide and differentiate into various sets of neurons and glial cells that roughly resemble the tissue elaboration in the fetal brain.
Secondly, infecting these neural organiods with Zika virus caused activation of Toll-like receptor 3 (TLR3). While this might seem like a foreign language to some of my readers, please hang with me and I will try to explain.
TLRs or Toll-Like Receptors bind to bits and pieces of invading fungi, bacteria, viruses, and parasites and alert the immune system to their presence. Pathogenic organisms have particular molecules collectively known as “Pathogen-Associated-Molecular-Patterns” or PAMPs and TLRs bind to various types of PAMPs.
Many non-immune cells, when their TLRs are activated, tend to give up the ghost and die, and that is precisely what happens to the neural progenitor cells in the neural organiods when they are infected by Zika virus. The infected neural stem cells kick the bucket (undergo programmed cell death) and the formation of new neurons and glial cells ceases.
The reduced formation of new neural cells means fewer neural tissues in the brain and smaller brains overall. Smaller brains also lead to smaller heads (microcephaly) and reduced mental capacity, sadly.
This article, by Jason Dang and others, shows that Zika virus might very well affect neural stem cells in the brain of the developing baby, which causes the deleterious effects on the brain of the new-born.
