Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice
1State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China.
Abstract:
The link between Zika virus (ZIKV) infection and microcephaly has raised urgent global alarm. The historical African ZIKV MR766 was recently shown to infect cultured human neural precursor cells (NPCs), but unlike the contemporary ZIKV strains, it is not believed to cause microcephaly. Here we investigated whether the Asian ZIKV strain SZ01 could infect NPCs in vivo and affect brain development. We found that SZ01 replicates efficiently in embryonic mouse brain by directly targeting different neuronal linages. ZIKV infection leads to cell-cycle arrest, apoptosis, and inhibition of NPC differentiation, resulting in cortical thinning and microcephaly. Global gene expression analysis of infected brains reveals upregulation of candidate flavirus entry receptors and dysregulation of genes associated with immune response, apoptosis, and microcephaly. Our model provides evidence for a direct link between Zika virus infection and microcephaly, with potential for further exploration of the underlying mechanisms and management of ZIKV-related pathological effects during brain development.
Insights
Asian Zika virus (ZIKV) strain SZ01 directly infects mouse embryonic brain cells, causing microcephaly. This study reveals ZIKV
Area of Science:
- Neuroscience
- Virology
- Developmental Biology
Background:
- Zika virus (ZIKV) infection is linked to microcephaly, raising global health concerns.
- While the African ZIKV MR766 strain infects neural precursor cells (NPCs), it's not associated with microcephaly.
- Contemporary ZIKV strains' impact on embryonic brain development requires further investigation.
Purpose of the Study:
- To investigate if the Asian ZIKV strain SZ01 can infect NPCs in vivo.
- To determine the effects of SZ01 infection on embryonic mouse brain development.
- To elucidate the molecular mechanisms underlying ZIKV-induced microcephaly.
Main Methods:
- Infection of embryonic mouse brains with ZIKV strain SZ01.
- Analysis of ZIKV replication and targeting of neuronal lineages.
- Assessment of NPC cell-cycle arrest, apoptosis, and differentiation.
- Global gene expression analysis of infected brain tissue.
Main Results:
- SZ01 efficiently replicates in the embryonic mouse brain, targeting various neuronal lineages.
- ZIKV infection induces cell-cycle arrest, apoptosis, and inhibits NPC differentiation.
- Cortical thinning and microcephaly were observed in infected mouse brains.
- Gene expression analysis revealed upregulation of flavivirus entry receptors and dysregulation of immune and apoptosis-related genes.
Conclusions:
- The Asian ZIKV strain SZ01 directly causes microcephaly in a mouse model by affecting neural development.
- This study provides a direct link between ZIKV infection and microcephaly, offering a model for further research.
- Findings suggest potential therapeutic targets for managing ZIKV-related pathological effects during brain development.
