Effect of Zika virus (ZIKV) sfRNA on host gene expression in human brain organoids
We employed 3D brain organoids generated from induced human pluripotent stem cells (ihPSC) as ex vivo model of viral infection in the developing brain and utilized wild type (WT) ZIKV producing sfRNA and mutant ZIKV deficient in production of sfRNA. Global transcriptome profiling by RNA-Seq revealed that production of sfRNA affects expression of >1000 genes. We uncovered that in addition to activation of pro-apoptotic pathways, organoids infected with sfRNA-producing WT, but not sfRNA-deficient mutant ZIKV, exhibited strong down-regulation of genes involved in signaling pathways that control neuron differentiation and brain develop-ment, which indicates the requirement of sfRNA for suppression of neurodevelopment associated with ZIKV infection. Using gene set enrichment analysis and gene network reconstruction, we demonstrated that the effect of sfRNA on pathways that control brain development occurs via crosstalk between Wnt-signaling and proapoptotic pathways. Overall design: Comparative gene expression profiling analysis of RNA-seq data for human brain organoids infected with WT and sfRNA-deficient ZIKV