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

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus that became widely recognized due to the epidemic in Brazil in 2015. Since then, there has been nearly a 20-fold increase in the incidence of microcephaly and birth defects seen among women giving birth in Brazil, leading the Centers for Disease Control and Prevention (CDC) to officially declare a causal link between prenatal ZIKV infection and the serious brain abnormalities seen in affected infants. Here, we used a unique rat model of prenatal ZIKV infection to study three possible long-term outcomes of congenital ZIKV infection: (1) behavior, (2) cell proliferation, survival, and differentiation in the brain, and (3) immune responses later in life. Adult offspring that were prenatally infected with ZIKV exhibited motor deficits in a sex-specific manner, and failed to mount a normal interferon response to a viral immune challenge later in life. Despite undetectable levels of ZIKV in the brain and serum in these offspring at P2, P24, or P60, these results suggest that prenatal exposure to ZIKV results in lasting consequences that could significantly impact the health of the offspring. To help individuals already exposed to ZIKV, as well as be prepared for future outbreaks, we need to understand the full spectrum of neurological and immunological consequences that could arise following prenatal ZIKV infection.

Sex‐specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways

“…Moreover, the capability of ZIKV to induce sex‐specific responses has been reported in different models in the literature 46,47 . We show evidence that sex‐specific differences may initiate in intrauterine life.…”

“…[43][44][45] Moreover, the capability of ZIKV to induce sex-specific responses has been reported in different models in the literature. 46,47 We show evidence that sex-specific differences may initiate in intrauterine life. The mechanisms by which the placenta supports fetal growth will likely differ between female and male fetuses within a litter, even in normal physiological mouse pregnancies.…”

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).…”

Assessing the role of Ndel1 oligopeptidase activity in congenital Zika syndrome: Potential predictor of congenital syndrome endophenotype and treatment response

“…Together, these abnormalities ultimately result in microcephaly (Vue and Tang, 2021). In prenatal ZIKV infection rat model, adult offspring that were prenatally infected with ZIKV failed to develop a normal interferon (IFN) response to a viral immune challenge, resulting in lasting consequences that could significantly impact the health of offspring later in life (Sherer et al, 2021).…”

“…Together, these abnormalities ultimately result in microcephaly (Vue and Tang, 2021). In prenatal ZIKV infection rat model, adult offspring that were prenatally infected with ZIKV failed to develop a normal interferon (IFN) response to a viral immune challenge, resulting in lasting consequences that could significantly impact the health of offspring later in life (Sherer et al, 2021). The immune evasion by ZIKV involves non‐structural proteins from virus, which modulate IFN signaling and production, and it can be critically strengthened by subverting the host immunity (Estévez‐Herrera et al, 2021).…”