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Zika causes neural stem cells to self-destruct

A new study reveals human neural stem cells infected with the Zika virus trigger an innate immune response that leads to cell death. The work is adding to the growing number of studies using brain organoids made from reprogrammed human embryonic stem cells to understand how the Zika virus leads to microcephaly.

On May 6 in Cell Stem Cell, University of California San Diego School of Medicine researchers report that if this immune response is blocked, it helps neural stem cells survive Zika infection.

Zika contributes to cell self-destruction by activating an infected brain cell's innate immune receptor TLR3, which has long been known to coax cells into producing antiviral proteins as a first line of defense against microbe invaders. Graduate student Jason Dang, whose research is in how TLR3 responds to different viruses, stumbled upon this connection when he tested TLR3 levels in Zika-infected brain organoids — developed in the lab of Tariq Rana at University of California San Diego, Biomedical Sciences Graduate Program.

"We were wondering how strong the evidence was, and we were excited when we saw that when we inhibit TLR3 in the Zika-infected brain organoids, the reduction in their size was less dramatic. I was still not convinced, so we used a chemical to enhance TLR3 activation and observed that the brain tissue started to shrink a lot faster."

Tariq Rana PhD, Professor of Pediatrics, University of California San Diego, Biomedical Sciences Graduate Program, and senior author.

Previous work with Zika-infected brain organoids helped establish the connection between viral infection and the death of neural stem cells, but Rana's team adds in a new piece about the role of the immune system. Inhibition of TLR3 may help neurons infected by Zika survive and continue to function as well as their uninfected counterparts, thus providing a target for therapeutic development.

"A part of my lab works on other viruses and we always look at macrophages and other external immune cells--we never would have thought to look at this system," Rana says. "There are many other viruses that cause central nervous system damage, and now I want to go back and look at those as well."

Abstract Summary
In summary, our results show direct effects of ZIKV on NPC development, including proliferation, differentiation, and cell death, which may link ZIKV with the development of microcephaly. Our study also provides insights into indirect effect of ZIKV infection on induced immune responses, including cytokine production and the effects of these cytokines on neural development. Moreover, the combination and comparison of our global transcriptome datasets of infected brains with that of hiPSCs (Tang et al., 2016) will provide valuable resources for further investigation of the underlying cellular and molecular mechanisms and management of ZIKV-related pathological effects during neural development.

This work was supported in part by grants from the National Institutes of Health.

Cell Stem Cell, Dang and Tiwari et al.: "Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3" http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)30057-1

Cell Press Statement on Data Sharing in Public Health Emergencies
The Cell Press family of journals is committed to ensuring that the global response to public health emergencies is informed by the best available research evidence and data, and as such, we will make all content concerning the Zika virus free to access. We will work in partnership with reviewers to fast-track review all submissions concerning Zika. We will adapt the editorial criteria that we apply to Zika submissions by asking reviewers to evaluate only if the research methods are sound and support the conclusions and if the work will contribute in some way toward resolving the immediate challenges. We will expedite publication of papers that meet these two criteria.

Cell Stem Cell (@CellStemCell), published by Cell Press, is a monthly journal that publishes research reports describing novel results of unusual significance in all areas of stem cell research. Each issue also contains a wide variety of review and analysis articles covering topics relevant to stem cell research ranging from basic biological advances to ethical, policy, and funding issues. Visit: http://www.cell.com/cell-stem-cell. To receive Cell Press media alerts, contact press@cell.com.
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May 17, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Zika virus (ZIKV) shortens growth in cerebral organoids made from human embryonic stem cells.
It targets neural progenitor cells — activating an immune response. This leads to dysregulation
of a network of genes involved in creation of new neurons, guidance of axons, apoptosis
(or cell death), and cell differentiation.
Image Credit: Dang and Tiwari et al./Cell Stem Cell 2015





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