Neuroteratogenic mechanisms of Zika virus (ZIKV) infection: Insights into fetal brain development disruption and congenital Zika syndrome: A systematic review

Abstract

The Zika virus (ZIKV), a mosquito-borne Flavivirus, has emerged as a global health threat due to its severe neuroteratogenic effects, particularly during pregnancy. This mechanistic-to-translational synthesis examines how ZIKV disrupts fetal brain development and links molecular events to clinical manifestations of Congenital Zika Syndrome (CZS). Our review advances prior summaries by presenting a unifying neural progenitor cell (NPC)-centric pathway framework that integrates viral entry, host signaling disruption, cell fate outcomes, and imaging correlates. Once transmitted vertically, the virus targets NPCs, impairing proliferation, triggering apoptosis, and halting the cell cycle. It modulates host pathways such as PI3K-Akt-mTOR and p53 to enhance autophagy, avoid immune detection, and sustain replication. ZIKV also interferes with RNA interference and synaptic formation, contributing to cortical thinning, ventriculomegaly, and agenesis of the corpus callosum. Inflammatory responses further exacerbate tissue damage as ZIKV activates TLRs and inflammasomes, increasing proinflammatory cytokines and pyroptosis. Brain organoid and imaging studies highlight the virus’s NPC tropism and capacity for lasting neurodevelopmental impairment—even in normocephalic infants. Importantly, ZIKV exhibits SOX2-dependent permissiveness with integrin αvβ5 functioning as a key dependency/attachment factor in neural and glioblastoma stem cells, distinguishing transcriptional state from receptor function. This intersection of neurotropism and potential oncolytic activity underscores the dual pathogenic and therapeutic implications of ZIKV. Literature was synthesized according to a predefined search strategy, with evidence appraised for quality, strengths, and limitations. This review highlights mechanistic pathways linking viral replication, immune modulation, and disrupted neurodevelopment, emphasizing implications for surveillance, therapeutic targets, and maternal-fetal health preparedness.