A Rat Model of Prenatal Zika Virus Infection and Associated Long-Term Outcomes
[Thesis]
Sherer, Morgan L.
Schwarz, Jaclyn M.
University of Delaware
2020
91 p.
Ph.D.
University of Delaware
2020
Zika virus (ZIKV) is a mosquito-borne flavivirus that was first isolated in 1947 from a rhesus macaque in Uganda (Cugola et al., 2016). ZIKV remained in relative obscurity for decades until 2007, when it caused its first noteworthy epidemic on Yap island in Micronesia, and then in 2013 when it reached New Caledonia, French Polynesia, and most extensively, Brazil in 2015 (Shao et al., 2016). 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 (Devhare, Meyer, Steele, Ray, & Ray, 2017; Mlakar et al., 2016; Retallack et al., 2016), 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 (Gladwyn-Ng et al., 2017). Since then, it has been hypothesized that microcephaly may just be the "tip of the iceberg" for neurological and cognitive consequences associated with this virus. In fact, pediatricians are now reporting an increased risk of seizures, irritability, and cognitive developmental delays in ZIKV affected children, some of whom appeared asymptomatic at birth (Kapogiannis, Chakhtoura, Hazra, & Spong, 2017; Wheeler, 2018). The population of children prenatally exposed during the 2015 Brazilian outbreak, would now be reaching the age of 5 or 6. Thus, the full spectrum of long-term biological and behavioral consequences associated with congenital ZIKV exposure have not been established. Here, we used our unique rat model of prenatal ZIKV infection to study the long-term impact of congenital ZIKV infection on behavior, cellular proliferation, survival, and differentiation, as well as on the immune system later in life. We found that adult offspring prenatally exposed to ZIKV demonstrated motor deficits in a sex specific manner and failed to mount a typical immune response to later-life infection. These results suggest that prenatal exposure to ZIKV results in lasting consequences that could be devastating to the health of the offspring. In order 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 exposure.