Understanding Zika virus-induced neuropathogenesis and neurotropism

Zika virus (ZIKV) evolved from an overlooked mosquito-borne flavivirus into a global health threat. However, the molecular mechanisms underlying this new ZIKV neuropathogenicity (e.g., microcephaly) are not understood. I hypothesise differences in tropism and inflammatory host responses, between African and American ZIKV lineages, underlie different pathologies in the developing brain. In a comprehensive approach, I will compare viral replication, viral gene expression, and host responses in a series of tractable models selected to reproduce the in vivo development of the human brain, including cerebral organoids. I will combine RNA sequencing and ribosome profiling methods established in my laboratory to measure virus and host responses, directly comparing African and American isolates. I will then test mechanistic hypotheses formed by manipulating host gene (RNAi/CRISPR-Cas9) or viral gene (reverse genetics mutants) expression and examining effects on virus replication and host response. This will also include the characterisation of the novel virulence factors I recently discovered to differ between African and American ZIKV. In this way, I will gain the most complete understanding of ZIKV inflammation mechanisms and pathogenesis drivers, and the functional viral genetics distinguishing African and American strains, to inform novel therapeutics and public health measures.