Protection of ZIKV infection-induced neuropathy by abrogation of acute antiviral response in human neural progenitors

Cell Death & Differentiation, 2019 · DOI: https://doi.org/10.1038/s41418-019-0324-7 · Published: April 5, 2019

Regenerative Medicine Immunology Neurology

Simple Explanation

This study investigates how Zika virus (ZIKV) infection leads to microcephaly in newborns by examining its effects on human neural progenitor cells (NPCs). Researchers found that ZIKV affects NPCs from different brain regions equally. The research indicates that ZIKV infection triggers an overactivated antiviral response in these cells, which unexpectedly harms their normal growth. This response involves specific genes activated independently of interferon (IFN) production. The study suggests that targeting this IFN-independent antiviral pathway could help reduce the neurological damage caused by ZIKV infection, offering a potential therapeutic avenue.

Study Duration

6 days post infection

Participants

Human neural progenitors (NPCs) derived from human pluripotent stem cells

Evidence Level

In vitro study using human cell lines

Key Findings

1
ZIKV efficiently infects human NPCs from various brain regions (forebrain dorsal, forebrain ventral, hindbrain, and spinal cord) derived from human embryonic stem cells.
2
ZIKV infection leads to growth arrest and programmed cell death in all regional NPCs, mirroring microcephaly pathology.
3
Overactivation of IFN-independent ISG pathways is detrimental to human NPCs, and blocking these pathways can protect against ZIKV-induced neuropathy.

Research Summary

The study examined the impact of Zika virus (ZIKV) on human neural progenitor cells (NPCs) derived from different brain regions, finding that ZIKV infects these cells similarly, leading to growth arrest and apoptosis. Transcriptome profiling revealed an overactivated antiviral response in NPCs upon ZIKV infection, specifically the activation of IFN-stimulated genes (ISGs) independent of interferon (IFN) production. Blocking the IFN-independent ISG pathway protected against ZIKV-induced neuropathy, suggesting this pathway as a potential therapeutic target to mitigate ZIKV infection's neurological effects.

Practical Implications

Therapeutic Target Identification

The IFN-independent acute antiviral pathway may serve as a potential target to ameliorate ZIKV infection-triggered neuropathy.

Understanding Microcephaly Pathology

Overactivated antiviral response is detrimental rather than protective in human NPCs, accounting for microcephaly pathology upon ZIKV infection.

Drug Development

Development of drugs that can abrogate intrinsic ISGs activation might serve a way to mitigate ZIKV infection-induced neuropathy.

Study Limitations

1
The study is conducted in vitro, and findings may not fully translate to in vivo conditions.
2
The specific mechanisms by which IRF3 and NF-κB contribute to ZIKV-induced neuropathy require further investigation.
3
The discrepancy between this study's findings regarding TLR3 and other studies needs to be addressed to fully understand the role of innate immune responses in ZIKV infection.

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