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Updated: Dec 22, 2025
Modelling Zika Virus Infection of the Developing Human Brain In Vitro Using Stem Cell Derived Cerebral Organoids
Published on: September 19, 2017
Basic insights into Zika virus infection of neuroglial and brain endothelial cells
Margit Mutso1, James A St John1,2,3, Zheng Lung Ling4
1Institute for Glycomics, Griffith University, Gold Coast Campus, Southport 4222, Queensland, Australia.
Abstract:
Zika virus (ZIKV) has recently emerged as an important human pathogen due to the strong evidence that it causes disease of the central nervous system, particularly microcephaly and Guillain-Barré syndrome. The pathogenesis of disease, including mechanisms of neuroinvasion, may include both invasion via the blood-brain barrier and via peripheral (including cranial) nerves. Cellular responses to infection are also poorly understood. This study characterizes the in vitro infection of laboratory-adapted ZIKV African MR766 and two Asian strains of (1) brain endothelial cells (hCMEC/D3 cell line) and (2) olfactory ensheathing cells (OECs) (the neuroglia populating cranial nerve I and the olfactory bulb; both human and mouse OEC lines) in comparison to kidney epithelial cells (Vero cells, in which ZIKV infection is well characterized). Readouts included infection kinetics, intracellular virus localization, viral persistence and cytokine responses. Although not as high as in Vero cells, viral titres exceeded 104 plaque-forming units (p.f.u.) ml-1 in the endothelial/neuroglial cell types, except hOECs. Despite these substantial titres, a relatively small proportion of neuroglial cells were primarily infected. Immunolabelling of infected cells revealed localization of the ZIKV envelope and NS3 proteins in the cytoplasm; NS3 staining overlapped with that of dsRNA replication intermediate and the endoplasmic reticulum (ER). Infected OECs and endothelial cells produced high levels of pro-inflammatory chemokines. Nevertheless, ZIKV was also able to establish persistent infection in hOEC and hCMEC/D3 cells. Taken together, these results provide basic insights into ZIKV infection of endothelial and neuroglial cells and will form the basis for further study of ZIKV disease mechanisms.
Insights
Zika virus infects brain endothelial and olfactory ensheathing cells, causing inflammation and persistent infections. Understanding these cellular responses is key to ZIKV neuroinvasion research.
Area of Science:
- Neurovirology
- Cellular and Molecular Biology
Background:
- Zika virus (ZIKV) is linked to severe neurological disorders like microcephaly and Guillain-Barré syndrome.
- Mechanisms of ZIKV neuroinvasion and cellular responses during infection remain poorly understood.
Purpose of the Study:
- To characterize ZIKV infection in human brain endothelial cells (hCMEC/D3) and olfactory ensheathing cells (OECs) in vitro.
- To compare ZIKV infection kinetics, localization, persistence, and cytokine responses in these cells versus Vero cells.
Main Methods:
- In vitro infection of hCMEC/D3, human and mouse OECs, and Vero cells with ZIKV strains.
- Analysis of viral titres, intracellular protein localization (envelope, NS3), dsRNA, and endoplasmic reticulum (ER) markers.
- Measurement of pro-inflammatory chemokine production.
Main Results:
- ZIKV achieved substantial titres (>10^4 pfu/ml) in endothelial and some neuroglial cells, though a small proportion were primarily infected.
- ZIKV proteins localized to the cytoplasm, overlapping with dsRNA and ER in infected cells.
- Infected endothelial and OEC cells produced high levels of pro-inflammatory chemokines and established persistent infections.
Conclusions:
- ZIKV can productively infect brain endothelial and olfactory ensheathing cells, inducing inflammatory responses.
- Persistent ZIKV infection in these neural and barrier cells suggests potential mechanisms for neuroinvasion and pathogenesis.
- These findings provide foundational insights for further investigation into ZIKV's impact on the central nervous system.
