SUMMARY / ABSTRACT The outbreak of Zika virus (ZIKV) and the alarming rise in fetal brain malformations highlight ZIKV as an urgent public health concern. ZIKV has recently met Shephard's criteria for teratogenic classification because of the brain anomalies reported. This application addresses the direct relationship between ZIKV infection and fetal brain development using our established fetal primate model of intrauterine pathogenesis. The studies outlined in this application leverage our prior discoveries and collaborative investigations on neural precursor cell function in relation to microglia in the fetal primate brain, and our expertise in primate development, imaging, virology, and immunology. Our track record and experienced team provides the means to pursue the goals of this proposal—understanding the mechanism(s) of ZIKV teratogenesis—and the steps necessary to progress to studies focused on interventions. Our goal is to determine how ZIKV alters cortical development by capitalizing on our team's essential expertise and research experiences to address this urgent public health concern rapidly and effectively through the following Specific Aims: (1) Define the impact of fetal ZIKV on neural precursor cells and cortical development, and (2) Determine the impact of fetal ZIKV infection on fetal and maternal inflammation and assess if inflammation is predictive of abnormalities in cortical development. These studies will provide new insights into the underpinnings of ZIKV teratogenesis in a primate model with similar neurodevelopmental features when compared to humans, and by efficiently leveraging an existing primate model of fetal viral infection. Overall, these investigations focus on fetal developmental outcomes associated with direct ZIKV infection and will provide the necessary mechanistic understanding and outcome metrics to assess intervention strategies that protect the fetus and newborn from the devastating consequences of ZIKV infection and congenital disease.

NARRATIVE These studies address the relationship between Zika virus infection and fetal development using established primate intrauterine pathogenesis and development models. These models recapitulate the clinical aspects of human congenital disease, and have facilitated the investigation of new vaccines and therapeutic interventions. The objective of the proposed studies is to address this urgent public health concern rapidly and effectively in a proven model of congenital infection that will provide critical information on how Zika virus impacts the developing brain and ensure an accelerated path to new treatments and interventions.