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 affects placental physiology and metabolic transport potential and impacts the fetal outcome, regardless of viral presence in the fetus at term. Low (103 PFU-ZIKVPE243; low ZIKV) and high (5x107 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 brain. Nevertheless, pregnancies in 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, less abundant microvilli and mitochondrial degeneration were evidenced in the placental labyrinth zone (Lz) of ICompromised and high-ZIKV-ICompetent mice but not in low-ZIKV-C57BL/6 mice. In addition, decreased placental expression of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) and the lipid transporter Abca1 was detected in all ZIKV-infected groups, but Bcrp and Abca1 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 manner 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.

Effect of Sublethal Prenatal Endotoxaemia on Murine Placental Transport Systems and Lipid Homeostasis

“…Consistent with our data, P-gp is downregulated in (1) human first trimester placental explants exposed to LPS (Lye et al, 2015), (2) human PTB placentae with chorioamnionitis (Do Imperio et al, 2018), (3) placentae from pregnant malariainfected C57BL/6 mice exhibiting high rates of PTB (Fontes et al, 2019), and (4) placentae from pregnant ZIKV-infected mice (Andrade et al, 2021). Furthermore, P-gp activity is impaired in the developing fetal blood brain barrier of pregnant C57BL/6 mouse exposed to PolyI:C, a TLR3 viral mimic (Bloise et al, 2017).…”

Altered Umbilical Cord Blood Nutrient Levels, Placental Cell Turnover and Transporter Expression in Human Term Pregnancies Conceived by Intracytoplasmic Sperm Injection (ICSI)

“…Slides were visualized with a high-resolution Olympus DP72 (Olympus Corporation, Tokyo, Japan) camera coupled to the Olympus BX53 light microscope (Olympus Corporation, Tokyo, Japan). Scoring of immunosignals was performed as previously described with adaptations [ 32 , 33 , 34 ], using STEPanizer software [ 35 ]. A total of 30 digital images were captured per placental fragment of each patient.…”

“…In each image, Ki-67 and TUNEL nuclei immunostaining were quantified and the resulting value was divided by the area of the total image, which yielded an estimate for the number of proliferative or apoptotic nuclei present in the whole tissue (number of nuclei/area of tissue). Quantification of GLUT 1, SNAT2, P-gp and BCRP immunostaining was performed using the Image Pro Plus 5.0 software (Media Cybernetics, Maryland, Rockville, MD, USA) mask tool, where immunostaining of the percentage area of viable tissue was quantified (with negative/empty spaces excluded) [ 32 , 33 , 34 ].…”

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

“…Cumulative evidence from our group and others, indicate that infection and inflammation may disrupt the syncytiotrophoblast (STB) barrier efficiency, impairing the expression and function of these transporters 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 rubella during pregnancy—compared with the general population 17 .…”