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Cell Stem Cell. 2016 Aug 4;19(2):258-65. doi: 10.1016/j.stem.2016.04.014. Epub 2016 May 6.

Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3.

Author information

1
Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
2
Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
3
Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
4
Bioinformatics core, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
5
Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: trana@ucsd.edu.

Abstract

Emerging evidence from the current outbreak of Zika virus (ZIKV) 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.

KEYWORDS:

Toll-like receptors; Zika virus; microcephaly; organoids

PMID:
27162029
PMCID:
PMC5116380
[Available on 2017-08-04]
DOI:
10.1016/j.stem.2016.04.014
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