Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3
Open accessAbstract
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.
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Forebrain organoid studies revealed cell-specific viral tropism, selective effects on neural progenitor cell proliferation, and upregulation of the innate immune receptor TLR3 after Zika virus infection.
“Further studies used forebrain organoids to reveal cell-specific viral tropism, selective effects on NPC proliferation5, and upregulation of the innate immune receptor Toll-like receptor 3 (TLR3) after ZIKV infection71.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [71]
Pathway analysis of gene expression changes during TLR3 activation highlighted genes related to neuronal development, suggesting a mechanistic link to disrupted neurogenesis.
“Pathway analysis of gene expression changes during TLR3 activation highlighted several genes related to neuronal development, suggesting a mechanistic connection to disrupted neurogenesis.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [71]
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- Authors
- Dang, J., Tiwari, S. K., Lichinchi, G., Qin, Y., Patil, V. S., Eroshkin, A. M., & Rana, T. M.
- Affiliations
- University of California San Diego (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Rana, Tariq M.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 19
- Issue
- 2
- Pages
- 258-265
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC5116380
- OpenAlex
- W2346484133
- Cited by
- 731
- References
- 38
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 54 · 2023: 50 · 2022: 62 · 2021: 98 · 2020: 66 · 2019: 77 · 2018: 109 · 2017: 103 · 2016: 55
- FWCI
- 113.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (DP1DA039562)
- National Cancer Institute (P30CA030199)
- National Institute of Allergy and Infectious Diseases (R01AI043198, R21AI125103)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Zika virus, brain organoids, TLR3, innate immunity, neural progenitor cells, microcephaly, neurogenesis, embryonic stem cells, neurospheres
- MeSH terms
- Zika Virus Infection, Zika Virus, Animals, Cell Differentiation, Fetus, Humans, Immunity, Innate, Organoids, RNA, Apoptosis, Toll-Like Receptor 3, Mice, Cerebrum, Neurogenesis, Neural Stem Cells
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