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

By Jason W. Dang, S. Tiwari, Gianluigi Lichinchi, Yue Qin, Veena S Patil, A. Eroshkin, T. Rana. Cell Stem Cell, 2016

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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.

Subfields: Epidemiology, Neurology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/5503493ec69fad34ebcc71a07aa05fea85cd6731

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Citations in the corpus

Brain organoids: advances, applications and challenges (2019, background): “For example, exposure of brain organoids to Zika virus results in preferential infection of NPCs, which suppresses proliferation and causes an increase in cell death, ultimately leading to drastically reduced organoid size (Cugola et al., 2016; Dang et al., 2016; Garcez et al., 2016; Qian et al., 20”