Mechanisms of Zika Virus Lineage-Dependent Pathogenesis Defined in Cerebral Organoids Derived from Human Embryonic Stem Cells

Zika viruses (ZIKV) have pandemic potential, with infections that cause serious human diseases, including microcephaly and Guillain-Barre syndrome. The pathogenesis properties of ZIKV lineages vary widely, and defining the underlying mechanisms has been complicated by the use of different cell-based and animal models to test ZIKV infections. The goal of this work was to define differential pathogenesis mechanisms among mild and severe ZIKV infections through comparative infections, using a relevant human stem cell-derived cerebral organoid experimental model system. ZIKV RNA does not persist in organoid ventricle cells during mild Asian/American lineage ZIKV infections; however, viral RNA persisted in ventricle cells during severe African lineage infections. The data suggest that mild and severe ZIKV lineages are differentiated in pathogenesis by host antiviral, interferon, and stress responses that cause apoptosis and oxidative stress. Stress-related hydroxyl radical damage to the organoids was partially blocked by Trolox, a hydroxyl radical scavenger drug, suggesting potential therapeutic benefit.