Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with microcephaly and other neurological disorders in infants born to infected mothers. Despite being declared an international emergency by the World Health Organization, very little is known about the mechanisms of ZIKV pathogenesis or the long-term consequences of maternal ZIKV infection in the affected offspring, largely due to the lack of appropriate rodent models. To address this issue, our lab has developed a working model of prenatal ZIKV infection in rats. In this study, we infected immune competent pregnant female rats with 105–107 PFU of ZIKV (PRVABC59, Puerto Rico/Human/Dec 2015) in order to examine its pathogenesis in the dams and pups. We examined the febrile response and sickness behavior in the dams, in addition to neonatal mortality, microglia morphology, cortical organization, apoptosis, and brain region-specific volumes in the offspring. Here, we demonstrate that pregnant and non-pregnant female rats have a distinct febrile response to ZIKV infection. Moreover, prenatal ZIKV infection increased cell death and reduced tissue volume in the hippocampus and cortex in the neonatal offspring. For the first time, we demonstrate the efficacy and validity of an immunocompetent rat model for maternal ZIKV infection that results in significant brain malformations in the neonatal offspring.

Highlights

  • Zika virus (ZIKV) is a mosquito-borne flavivirus that was first isolated in 1947 from a rhesus macaque in Uganda [1]

  • Data from non-pregnant and pregnant females were analyzed as a percent increase in body temperature from the body temperature of diluent-treated females, and analyzed using a two-way analysis of variance (ANOVA) for pregnancy condition and ZIKV dose as factors

  • Our results demonstrate that subcutaneous ZIKV injection of pregnant female rats is able to gain access to the fetal compartment and significantly impact the developing brain of the affected offspring, despite minimal symptoms in the dam

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Summary

Introduction

Zika virus (ZIKV) is a mosquito-borne flavivirus that was first isolated in 1947 from a rhesus macaque in Uganda [1]. ZIKV remained primarily a primate pathogen for decades, sporadically infecting humans until 2007, when it caused its first noteworthy human epidemic on the Yap islands in Micronesia, and in 2013 when it reached New Caledonia, French Polynesia, and more extensively, Brazil in 2015 [2]. Active transmission of ZIKV has been reported in over 70 countries and territories globally ZIKV infection during pregnancy is associated with an increased incidence of congenital malformations in the developing fetus, most notably, microcephaly.

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