Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways

Abstract Maternal Zika virus (ZIKV) infection during pregnancy can associate with severe intrauterine growth restriction (IUGR), placental damage, and metabolism disturbance, as well as newborn neurological abnormalities. Here, we investigated whether maternal ZIKV infection affects placental nutrient transporters and nutrient-sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (10 3 PFU-ZIKV PE243 ) and High (5×10 7 PFU-ZIKV PE243 ) ZIKV titers at gestational day (GD) 12.5, for tissue collection at GD18.5 (term). Feto-placental growth of male fetuses was dramatically affected by ZIKV, whereas no differences were observed in female fetuses. ZIKV promoted increased expression of glucose transporter type 1 ( Slc2a1 /Glut1) and decreased levels of glucose-6-phosphate in female placentas, with no differences in amino-acid transport potential. In contrast, glucose transport in male placentas was not affected by ZIKV, whilst a decreased placental protein expression of sodium-coupled neutral amino acid 2 (Snat2) was detected in the male low-dose ZIKV-infected group. There were also sex-dependent differences in the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation in ZIKV infected pregnancies, showing that ZIKV can cause disturbance in the nutrient handling in the placental tissue. Our findings thus identify relevant molecular alterations in the placenta caused by maternal ZIKV infection related to nutrient transport and availability. Notably, our results suggest that female and male placentas adopt different strategies to cope with the altered metabolic state caused by ZIKV. This may have relevance for understanding the effects of congenital Zika syndrome and could potentially assist future therapeutic strategies. Author Summary The Zika virus (ZIKV) has emerged as a major global health concern in the past decade. ZIKV infection during pregnancy can cause infants to be born with microcephaly and fetal growth restriction, among other pregnancy complications. Currently, the number of cases of ZIKV disease declined onwards globally. However, transmission persists at low levels in several countries in the Americas and other endemic regions, with neither a licensed vaccine nor an antiviral drug available for prevention and treatment. Here, we use a mice model of maternal ZIKV infection to analyze placental nutrient transporters and nutrient-sensitive pathways as a potential link to the complications related to congenital ZIKV infection. We found that feto-placental growth of male fetuses was dramatically affected by ZIKV, whereas no differences were observed in female fetuses. We also found that placental nutrient transporters and nutrient-sensitive pathways were altered in response to ZIKV infection, depending on the fetal sex. Our study presents relevant molecular alterations caused by maternal ZIKV infection and suggests that female and male placentas adopt different strategies in response to the altered environment caused by ZIKV. Our observations may have relevance for understanding the effects of ZIKV infection and could potentially assist future therapeutic strategies.