Mosquitoes spread Zika virus.
The summer 2016 Olympics are rapidly approaching and I’ve already been blown away by preview clips of some of the competing athletes performing amazing (and kind of dangerous!) looking stunts. Clouding this year’s games, however, has been the Zika virus outbreak, for which Brazil is at the epicentre.
While Zika virus has been seen in parts of Asia and Africa as far back as the 1940s, it is the recent outbreak in Latin and South America that has raised the global alarm, particularly because of the finding that Zika infection can lead to microcephaly – or underdeveloped brains – in newborn children.
My sympathies go out to the families and children affected by this virus. Although the tissue-engineering field cannot reverse what has happened in these individuals, a recent study may provide key insight as to how the Zika virus causes such effects.
In a study currently published online in Cell Stem Cell, Dr. Tariq Rana’s group out of UCSD used engineered human brain organoids to probe the mechanisms by which Zika infection may alter brain development.
Dr Rana’s group was able to use embryonic stem cells to engineer human cerebral organoids, which showed complex internal anatomy and the capacity for ion flux in response to excitatory neurotransmitters. They then compared the gene expression profile of their cerebral organoids to post-mortem fetal brain tissues and concluded their organoids best model early trimester fetal brain.
Having characterized their organoids, they infected them with the original MR766 ZIKV strain from Uganda. Not surprisingly, infected organoids experienced stunted growth, and even shrinkage, in comparison to mock-treated organoids. Staining for specific proteins showed Zika virus envelope proteins co-localized within the neural progenitor cell population, and these cells morphologically looked like they were undergoing cell death.
The question remains: how does Zika virus cause such cell death to occur?
Past studies in the literature indicate that Zika virus, along with related viruses, can increase the gene expression and activate a pathogen recognition receptor called Toll-like receptor 3 (TLR3). TLRs are an important mechanism by which we can detect foreign organisms and initiate many downstream responses, and Dr. Rana’s group wondered whether one such response could lead to death of neural progenitor cells (apoptosis of infected cells could be a natural defense mechanism).
To test this, his group exposed the cerebral organoids to a known TLR3 agonist, which demonstrated similar organoid shrinkage when infected with Zika virus. On the flip side, organoids infected with Zika virus, but exposed to a TLR3 inhibitor, had less substantial tissue loss.
Altogether, his studies suggest that Zika infection may stunt neural development by causing a TLR3-mediated apoptotic (cell death) response in developing brain tissue.
Previous Signals’ blogs have described the use of engineered neural tissue to study neurodegeneration and species differences in cognition. Dr. Rana’s study suggests another fascinating application, as engineered tissues may provide rapidly available disease modeling and drug testing platforms in the setting of new outbreaks of human infectious disease. My hope is that this work inspires similar studies in the future and will move us closer to a triumphant finish in our race to stop suffering from Zika infection.
Holly Wobma
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