Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly

Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain. [Display omitted] •Multi-omics analysis revealed key molecular pathways in congenital Zika syndrome•JAK/STAT activation is a potential driver of deranged brain development•Genes associated with microcephaly were downregulated in ZIKV-infected mouse brains•ZIKV load and cell cycle-inducing protein levels showed a negative correlation Immunology; Virology; Developmental neuroscience