UC Santa Barbara

Zika virus (ZIKV), a mosquito-borne flavivirus, causes severe congenital eye disease. However, the molecular mechanisms underlying retinal pathologies are largely unknown in human modeling. This dissertation explores the mechanisms of viral pathogenesis in the retina using stem cell-derived retinal organoids (ROs) as a model for Zika virus (ZIKV) and other retinal-targeting herpes simplex virus 1 (HSV1) infections. Utilizing immature ROs, we elucidate specific impacts of early trimester ZIKV infections on retinal progenitor and ganglion cells, demonstrating significant disruptions to organoid growth and health. Our findings underscore the critical role of the AXL receptor in mediating retinal ZIKV infection, suggesting its potential as a therapeutic target. Conversely, modeling with mature ROs reveals the rapid and destructive pathogenesis of HSV1, highlighting the vulnerability of photoreceptor and Müller glial cells to adult retinal necrotizing infections.Further, through single-cell RNA sequencing (scRNA-seq), we reveal distinct cellular responses to ZIKV and HSV1, including unique gene expression patterns associated with cellular stress responses and interferon signaling. Specifically, our work details the modulation of the unfolded protein response (UPR) by ZIKV infection and identifies key pharmacological targets for inhibiting viral replication and enhancing cell viability. Additionally, we demonstrate the potent antiviral effects of interferon-alpha and beta in ZIKV-infected ROs, emphasizing the importance of bystander immune stimulation. Our findings provide a nuanced understanding of retinal viral infections, offering novel insights into the highly complex cellular and molecular underpinnings of ZIKV pathogenesis in the retina and underscoring the value of retinal organoids as a model system for studying infectious diseases.