ZIKV disrupts fetal outcome, placental ultrastructure and drug transporter expression in mice

Congenital Zika virus (ZIKV) infection can induce fetal brain abnormalities. Here, we investigated whether maternal ZIKV infection may affect placental physiology and metabolic transport potential, and impact the fetal outcome, regardless of viral presence in the fetus at term. Low (10 3 PFU-ZIKVPE243; low-ZIKV) and high (5x10 7 PFU-ZIKVPE243; high-ZIKV) virus titers were injected into immunocompetent (ICompetent C57BL/6) and immunocompromised (ICompromised A129) mice at gestational day (GD)12.5 for tissue collection at GD18.5 (term). High-ZIKV elicited fetal death rates of 66% and 100%, whereas low-ZIKV induced fetal death rates of 0% and 60% in C57BL/6 and A129 dams, respectively. All surviving fetuses exhibited intrauterine growth restriction (IUGR) and decreased placental efficiency. High-ZIKV infection in C57BL/6 and A129 mice resulted in virus detection in maternal spleens and placenta, but only A129 fetuses presented virus RNA in the brains. Nevertheless, pregnancies of both strains produced fetuses with decreased head sizes (p<0.05). Low-ZIKV-A129 dams had higher IL-6 and CXCL1 levels (p<0.05) and their placentas showed increased CCL-2 and CXCL-1 contents (p<0.05). In contrast, low-ZIKV-C57BL/6 dams had an elevated CCL2 serum level, and increased type I and II IFN expression in the placenta. Notably, increased apoptotic rates, less abundant microvilli and mitochondrial degeneration were evidenced in the placental labyrinth (Lz) of ICompromised and high-ZIKV-ICompetent mice, but not in low-ZIKV-C57BL/6. In addition, decreased placental expression of the drug P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and the lipid ABCA1 transporters was detected in all ZIKV-infected groups, but BCRP and ABCA-1 were only reduced in ICompromised and high-ZIKV ICompetent mice. Our data indicate that gestational ZIKV infection triggers specific proinflammatory responses and affects placental turnover and transporter expression, in a way dependent on virus concentration and maternal immune status. Placental damage may impair proper fetal-maternal exchange function and fetal growth/survival, likely contributing to congenital Zika syndrome.