Deciphering the interplay between Zika virus and the human brain at a high resolution in twins discordant for CONGENITAL ZIKA SYNDROME

• Grant number: 24/01473-4
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: July 01, 2024
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Mayana Zatz
• Grantee: Raiane de Oliveira Ferreira
• Supervisor: Shirit Einav
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Stanford University, United States
• Associated to the scholarship: 20/14109-8 - Study of the oncolytic effect of Zika Virus on cells in the central nervous system tumor micro-environment, BP.DD

Abstract

Zika Virus (ZIKV), a mosquito-borne flavivirus, has attracted attention due to its impact on the central nervous system (CNS), causing severe brain anomalies during human embryonic development, known as Congenital Zika Syndrome (CZS). This BEPE proposal aims to unravel the intricate dynamics of ZIKV infection susceptibility and transcriptional expression in neural cells at different maturation stages, using cells derived from CZS discordant twins. These unique samples will allow us to compare responses from individuals exposed to ZIKV infection during pregnancy, with at least one of the babies born with CZS. Thus, we can enhance our understanding of the cellular and molecular mechanisms that increase susceptibility of affected individuals to the neurological effects of ZIKV. We hypothesize that infection by various ZIKV strains induces epigenetic and transcriptomic alterations, facilitating viral entry and replication while modifying the gene expression profile associated with brain development pathways and immune response in neural cells of individuals affected by CZS. To test this hypothesis, we will collaborate with the Einav Lab, which has developed the viscRNA-Seq (virus-inclusive single cell RNA-Seq) technique, capable of associating single-cell RNA-Seq with viral RNA quantification in the same cell. Our first aim is to characterize the susceptibility of different stages of neural cells and brain organoid (with microglia) to infection with two ZIKV strains--ZIKVBR (Brazilian strain) and ZIKV766 (African strain) and the viral replication kinetics. Our second aim is to profile the cellular transcriptome expression in correlation with viral abundance in multiple distinct cell types in cortical brain organoids (with microglia) infected with the distinct ZIKV strains used in the aim 1. Impact: This project is designed to provide novel insight into the pathogenesis of congenital ZIKV infection. Moreover, this project may lead to the discovery of cellular factors as candidate targets for biomarkers or countermeasures to predict development of CZS and/or prevent or treat it. Beyond the virology field, this project will assess the therapeutic potential and safety of using ZIKV as an oncolytic virus-an attractive approach proposed by recent studies showing ZIKV's capacity to target and eliminate cells in primary CNS tumors.