Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy

Abstract

Neuronal progenitor subtypes have distinct fate restrictions regulated by time-dependent activation of energetic pathways during development. Thus, the hijacking of cellular metabolism by Zika virus (ZIKV) to support its replication may contribute to damage in the developing fetal brain. Here, we showed that 2D in vitro differentiation of human induced pluripotent stem cells into cortical neuronal progenitors (hi-NPCs) produces metabolically distinct populations that resemble the metabolic profile of forebrain progenitor subtypes. These progenitor subtypes showed differential replication rates of neurotropic ZIKV. This differential replication alters the transcription of metabolic genes and upregulates the glycolytic capacity of progenitor subtypes. Analysis using Imagestream revealed subtype-specific metabolic alterations at different stages during ZIKV replication. During early stages of infection, ZIKV replication in early progenitors increases lipid droplet abundance and decreases mitochondrial size and membrane potential. During later stages infection, early progenitors show increased subcellular distribution of lipid droplets, whilst late progenitors show decreased mitochondria size. The finding that there are hi-NPC subtype-specific alterations of cellular metabolism during ZIKV infection provide a platform to investigate the mechanisms on how ZIKV differentially dysregulate the metabolism of forebrain progenitor subtypes which may help explain the differences in brain damage over each trimester.