PMID- 34093581 OWN - NLM STAT- MEDLINE DCOM- 20211025 LR - 20240402 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - ZIKV Disrupts Placental Ultrastructure and Drug Transporter Expression in Mice. PG - 680246 LID - 10.3389/fimmu.2021.680246 [doi] LID - 680246 AB - 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 (10(3) PFU-ZIKV(PE243); low ZIKV) and high (5x10(7) PFU-ZIKV(PE243); 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. CI - Copyright (c) 2021 Andrade, Monteiro, Coelho, Gomes, Sousa, Nascimento, Bloise, Matthews, Bloise, Arruda and Ortiga-Carvalho. FAU - Andrade, Cherley Borba Vieira AU - Andrade CBV AD - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Monteiro, Victoria Regina de Siqueira AU - Monteiro VRS AD - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Coelho, Sharton Vinicius Antunes AU - Coelho SVA AD - Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Gomes, Hanailly Ribeiro AU - Gomes HR AD - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Sousa, Ronny Paiva Campos AU - Sousa RPC AD - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Nascimento, Veronica Muller de Oliveira AU - Nascimento VMO AD - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Bloise, Flavia Fonseca AU - Bloise FF AD - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Matthews, Stephen Giles AU - Matthews SG AD - Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. AD - Department of Obstetrics & Gynecology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. AD - Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. AD - Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. FAU - Bloise, Enrrico AU - Bloise E AD - Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil. FAU - Arruda, Luciana Barros AU - Arruda LB AD - Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. FAU - Ortiga-Carvalho, Tania Maria AU - Ortiga-Carvalho TM AD - Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. LA - eng GR - 148368/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210521 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (Biomarkers) SB - IM MH - ATP-Binding Cassette Transporters/*genetics/metabolism MH - Animals MH - Apoptosis MH - Biomarkers MH - Female MH - Gene Expression MH - Host-Pathogen Interactions/genetics/immunology MH - Immunity MH - Immunocompromised Host MH - Immunohistochemistry MH - Male MH - Mice MH - Placenta/*ultrastructure/*virology MH - Pregnancy MH - *Pregnancy Complications, Infectious MH - Zika Virus/*physiology MH - Zika Virus Infection/*genetics/pathology/*virology PMC - PMC8176859 OTO - NOTNLM OT - ABCA1 OT - ABCG1 OT - P-glycoprotein (P-gp) breast cancer resistance protein (BCRP) OT - ZIKV OT - chemokine 2 OT - cytokine OT - placenta OT - ultrastructure COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/06/08 06:00 MHDA- 2021/10/26 06:00 PMCR- 2021/01/01 CRDT- 2021/06/07 05:50 PHST- 2021/03/13 00:00 [received] PHST- 2021/04/30 00:00 [accepted] PHST- 2021/06/07 05:50 [entrez] PHST- 2021/06/08 06:00 [pubmed] PHST- 2021/10/26 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.680246 [doi] PST - epublish SO - Front Immunol. 2021 May 21;12:680246. doi: 10.3389/fimmu.2021.680246. eCollection 2021.