Zika virus infections of human stem cell-derived cerebral organoids reveal viral lineage-specific pathogenesis responses
Name
harding-et-al-2026-zika-virus-infections-of-human-stem-cell-derived-cerebral-organoids-reveal-viral-lineage-specific.pdf
Description
Published version
Size
7.94 MB
Format
Adobe PDF
Checksum (MD5)
456e8c052781303ac4f989763828d565
Author(s)
Harding, Alfred T
Zhang, Yichen
Chen, Jane-Jane
Antonucci, Jenna M
Richards, Alexsia
Leger, Valerie
Whittaker, Charles A
Vanrobaeys, Yann S
Agarwal, Divyansh
Lungjangwa, Tenzin
Date Issued
June 15, 2026
Journal
mBio
Publisher
American Society for Microbiology
Citation
Harding AT, Zhang Y, Chen J, Antonucci JM, Richards A, Leger V, Whittaker CA, Vanrobaeys YS, Agarwal D, Lungjangwa T, Jaenisch R, Gehrke L. 2026. Zika virus infections of human stem cell-derived cerebral organoids reveal viral lineage-specific pathogenesis responses.
Version
Final published version
Abstract
Zika virus (ZIKV) has multiple lineages and strains that cause a range of disease severity, underscoring the need to elucidate differential neuropathogenesis mechanisms. Here, we performed systematic, side-by-side comparisons of African, Asian, and American ZIKV lineage infections using cerebral organoids derived from human embryonic stem cells, a relevant human model experimental system. African lineage ZIKV strains, as well as the ancestral Asian Malaysia strain, persistently infected neural progenitor cells, causing apoptosis and severe disruption of ventricular cytoarchitecture. In contrast, contemporary Asian and American lineage viruses were cleared from ventricles, coinciding with low apoptosis and reduced neuropathology. Single-cell RNA sequencing demonstrated upregulated cell-type-specific antiviral signaling during American lineage infections, coinciding with viral clearance from ventricular progenitor cells. Conversely, pathogenic African lineage infections were associated with apoptosis, reduced STAT2 and IFIT1 protein levels, and enhanced activation of stress pathways. African lineage and ancestral Malaysian strain infections induced mitochondrial oxidative stress. Scavenging the reactive oxygen species improved ventricular cytoarchitecture and progenitor survival, but without reducing viral titers. Together, these findings suggest that lineage- and strain-specific host stress responses, rather than viral burden alone, contribute to ZIKV-induced neurodevelopmental damage. An implication of this study is that host-directed therapeutic strategies, used to improve host tolerance to viral infection, may benefit clinical outcomes.
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DOI of Published Version
https://doi.org/10.1128/mbio.00863-26
