Stem cells to block Zika Virus

(Stem Cells News image)

Dang et al. show that Zika virus (ZIKV) attenuates growth in cerebral organoids from human embryonic stem cells by targeting neural progenitors. ZIKV activates the TLR3-mediated innate immune response, leading to dysregulation of a network of genes involved in neurogenesis, axon guidance, apoptosis, and differentiation.
Emerging evidence from the current outbreak of Zika virus indicates a strong causal link between Zika and microcephaly. To investigate how ZIKV infection leads to microcephaly, we used human embryonic stem cell-derived cerebral organoids to recapitulate early stage, first trimester fetal brain development.
Here we show that a prototype strain of ZIKV, MR766, efficiently infects organoids and causes a decrease in overall organoid size that correlates with the kinetics of viral copy number.
The innate immune receptor Toll-like-Receptor 3 (TLR3) was upregulated after ZIKV infection of human organoids and mouse neurospheres and TLR3 inhibition reduced the phenotypic effects of ZIKV infection.
Pathway analysis of gene expression changes during TLR3 activation highlighted 41 genes also related to neuronal development, suggesting a mechanistic connection to disrupted neurogenesis. Together, therefore, our findings identify a link between ZIKV-mediated TLR3 activation, perturbed cell fate, and a reduction in organoid volume reminiscent of microcephaly (…)
read more:cell.com/pb-assets/journals/research/stem/stem1984.pdf
The U.S. Centers for Disease Control and Prevention recently concluded that Zika virus infection in pregnant women can stunt neonatal brain development, leading to babies born with abnormally small heads, a condition known as microcephaly. Now, for the first time, researchers at University of California San Diego School of Medicine have determined one way Zika infection can damage developing brain cells. The study, published May 6 in Cell Stem Cell, also shows that inhibiting this mechanism reduces brain cell damage, hinting at a new therapeutic approach to mitigating the effects of prenatal Zika virus infection.
Using a 3D, stem cell-based model of a first-trimester human brain, the team discovered that Zika activates TLR3, a molecule human cells normally use to defend against invading viruses. In turn, hyper-activated TLR3 turns off genes that stem cells need to specialize into brain cells and turns on genes that trigger cell suicide. When the researchers inhibited TLR3, brain cell damage was reduced in this organoid model.
“We all have an innate immune system that evolved specifically to fight off viruses, but here the virus turns that very same defense mechanism against us,” said senior author Tariq Rana, PhD, professor of pediatrics at UC San Diego School of Medicine. “By activating TLR3, the Zika virus blocks genes that tell stem cells to develop into the various parts of the brain. The good news is that we have TLR3 inhibitors that can stop this from happening.”
In the study, Rana’s team first made sure their organoid model was truly representative of the early developing human brain. They found that the model’s stem cells differentiate (specialize) into the various cells of the brain in the same way that they do in the first trimester of human development (…)
read more:health.ucsd.edu/news/releases/Pages/2016-05-06-zika-virus-and-microcephaly.aspx

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