ZIKV disrupts placental ultrastructure and drug transporter expression in mice

Abstract

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 (103 PFU-ZIKVPE243; low-ZIKV) and high (5×107 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.

Mid-pregnancy poly(I:C) viral mimic disrupts placental ABC transporter expression and leads to long-term offspring motor and cognitive dysfunction

“…However, in recent studies we demonstrated speci c and independent responses of labyrinth and junctional zones. [11][12][13] In the present study, we showed that poly(I:C) affects both the labyrinth and junctional zones, causing region speci c placental remodeling. Further, ABC transporters levels in these two placental regions were affected in an opposite way following poly(I:C) treatment, reinforcing the importance of investigating these two zones separately.…”

“…41 Previous studies have shown poly(I:C) treatment on GD13.5 in the pregnant rat to decrease placental weight, area and thickness. 42 Of all the studies involving gestational infections by different pathogens and viral mimics from our group [11][12][13] , poly(I:C) was not able to affect fetal weight and the fetal weight/placental weight ratio.…”

“…With regard to the Jz, because it is primarily responsible for the endocrine function of the placenta 8,9 , an increase in cell death in this region may be affecting the hormonal biodistribution at the maternal-fetal interface. Comparing with mid-pregnancy zika virus (ZIKV) infection 12 , in poly(I:C) group the cell proliferation was the opposite of both ZIKV's high and low dose in the Lz, whereas cell death was similar to low dose. In the Jz, both poly(I:C) and ZIKV infection did not affect cell proliferation but did increase cell death in both poly(I:C) and high dose of ZIKV.…”

“…4,10−14 However, there is limited information on the impact elicited by acute mid-pregnancy viral infections on the expression of ABC transporters in the different compartments of the placenta at term. 12,15,16 It has been well established that maternal viral infection can affect placental function, which may result in pregnancy complications such as miscarriage or intrauterine growth restriction (IUGR), preterm birth and birth defects in the offspring. 12,17,18 Pregnant women are at greater risk of zika (ZIKV), cytomegalovirus (CMV) and herpes simplex viral infections, while exhibiting higher mortality rates when infected with H1N1, varicella and rubeola during pregnancy -compared with the general population.…”

“…12,15,16 It has been well established that maternal viral infection can affect placental function, which may result in pregnancy complications such as miscarriage or intrauterine growth restriction (IUGR), preterm birth and birth defects in the offspring. 12,17,18 Pregnant women are at greater risk of zika (ZIKV), cytomegalovirus (CMV) and herpes simplex viral infections, while exhibiting higher mortality rates when infected with H1N1, varicella and rubeola during pregnancy -compared with the general population. 17 Importantly, several studies have highlighted the key role of the placenta in the development of neuropsychiatric disorders in offspring.…”