An Examination of the Long-Term Neurodevelopmental Impact of Prenatal Zika Virus Infection in a Rat Model Using a High Resolution, Longitudinal MRI Approach

Abstract

Since Zika virus (ZIKV) first emerged as a public health concern in 2015, our ability to identify and track the long-term neurological sequelae of prenatal Zika virus (ZIKV) infection in humans has been limited. Our lab has developed a rat model of maternal ZIKV infection with associated vertical transmission to the fetus that results in significant brain malformations in the neonatal offspring. Here, we use this model in conjunction with longitudinal magnetic resonance imaging (MRI) to expand our understanding of the long-term neurological consequences of prenatal ZIKV infection in order to identify characteristic neurodevelopmental changes and track them across time. We exploited both manual and automated atlas-based segmentation of MR images in order to identify long-term structural changes within the developing rat brain following inoculation. The paradigm involved scanning three cohorts of male and female rats that were prenatally inoculated with 107 PFU ZIKV, 107 UV-inactivated ZIKV (iZIKV), or diluent medium (mock), at 4 different postnatal day (P) age points: P2, P16, P24, and P60. Analysis of tracked brain structures revealed significantly altered development in both the ZIKV and iZIKV rats. Moreover, we demonstrate that prenatal ZIKV infection alters the growth of brain regions throughout the neonatal and juvenile ages. Our findings also suggest that maternal immune activation caused by inactive viral proteins may play a role in altered brain growth throughout development. For the very first time, we introduce manual and automated atlas-based segmentation of neonatal and juvenile rat brains longitudinally. Experimental results demonstrate the effectiveness of our novel approach for detecting significant changes in neurodevelopment in models of early-life infections.

Prenatal Zika virus infection has sex-specific effects on infant physical development and mother-infant social interactions

“…Although multiple rodent models of ZIKV exist (15)(16)(17)(18)(19), NHP models of ZIKV and fZIKV remain best suited for modeling human neurological and psychological development because of both limitations of the rodent models and strengths of the NHP model. NHPs, such as monkeys from the genus Macaca, demonstrate transplacental transmission of the ZIKV to the fetus (20)(21)(22)(23) and also share many homologies in terms of cortical structure and function with humans (24).…”

Special Issue “Pediatric Viral Infection Long-Term Consequences”

“…Studies in this issue contributed to our knowledge of congenital Zika virus infection, with manuscripts utilizing animal models in rats and nonhuman primates, and a human clinical study. A new rat model of prenatal Zika virus infection described novel automated atlas-based segmentation of MR images and found that prenatal Zika virus infection alters the growth of brain regions throughout neonatal and juvenile ages [1]. A nonhuman primate model of prenatal Zika virus infection explored the impact of maternal Dengue virus immunity on neonatal development, identifying that maternal Dengue virus immunity exacerbates Zika-induced visual orientation and tracking deficits [2].…”