Zika virus infection of pregnant rats and associated neurological consequences in the offspring

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 10 5 –10 7 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.

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

“…ZIKV infection causes apoptosis [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. We therefore asked whether reduced innate immune recognition of ZIKV in RIG-I KO cells impacts virus-induced cell death.…”

Animal models of congenital zika syndrome provide mechanistic insight into viral pathogenesis during pregnancy

“…Rats have been used to study CZS as they naturally exhibit an immunocompromised phenotype during pregnancy, particularly during late gestation, similar to humans [ 71 ]. Following subcutaneous ZIKV inoculation, pregnant rats do not developed signs of sickness, but the pups show reduced hippocampal and cortical volumes with preliminary evidence of cerebro-cortical dysplasia [ 72 ]. However, as the presence of live, replicating virus was not confirmed within the dams or pups, whether these effects were directly mediated by the virus or by secondary mechanisms like activation of the maternal immune response remains unknown.…”

A Rat Model of Prenatal Zika Virus Infection and Associated Long-Term Outcomes

“…These data, along with previous findings from our lab which demonstrate reduced pup mortality, increased apoptosis, and cerebrocortical dysplasia in rat pups prenatally exposed to ZIKV [35] have led us to hypothesize that prenatal ZIKV exposure may permanently alter cellular proliferation, survival, and decrease life-long neurogenesis in the dentate gyrus of the hippocampus. We hypothesized that this could be caused by either persistent ZIKV residence in the brain, or alternatively by ZIKV-induced decreases in the NPC population early in life.…”

“…Pregnant females were inoculated through subcutaneous injection on their dorsum on E18 with either a diluent control (0.1 mL of the same culture media used to grow ZIKV) or ZIKV (dose of 107 PFU in 0.1 mL culture media). Embryonic time point and ZIKV dose were selected based on work that was previously published in our lab [35]. Immediately following injections rats were returned to their home cage and left undisturbed until the start of additional experimental procedures.…”