Zika virus (ZIKV) infection during pregnancy is linked to severe birth defects, but mother-to-fetus transmission routes are unknown. We infected different primary cell types from mid- and late-gestation placentas and explants from first-trimester chorionic villi with the prototype Ugandan and a recently-isolated Nicaraguan ZIKV strain. ZIKV infects primary human placental cells and explants – cytotrophoblasts, endothelial cells, fibroblasts and Hofbauer cells in chorionic villi and amniotic epithelial cells, and trophoblast progenitors in amniochorionic membranes expressing Axl, Tyro3 and/or TIM1 viral entry cofactors. ZIKV produced NS3 and E proteins and generated higher viral titers in amniotic epithelial cells from mid-gestation compared to late-gestation placentas. Duramycin, a peptide that binds phosphatidylethanolamine in enveloped virions and precludes TIM1 binding, reduced ZIKV infection in placental cells and explants. Our results suggest that ZIKV spreads from basal and parietal decidua to chorionic villi and amniochorionic membranes, and targeting TIM1 could suppress infection at the uterine-placental interface.

Figure 8. Effects of placental sFlt1 knockdown with or without endometrial VEGF overexpression. (A-L) Placental sFlt1 knockdown. Upon placentaspecific sFLT1 shRNA expression, widespread hemorrhaging in the fetus (B) and at the placental-decidual junction (D) was observed on GD18 compared with controls (A and C). Histological examination of sFLT1 shRNA-expressing placentas revealed extraordinary dilation of some maternal blood sinuses (arrowheads) in the labyrinth (E and F) and fibrin deposition (arrow) in these spaces (G and H). (I and J) MSB staining revealed extravasated fibrin (arrow) in adjacent areas. Placental sFlt1 knockdown did not affect implantation rate (K), whereas the fetal resorption rate significantly increased (L). (M-V) Placental sFlt1 knockdown enhanced the deleterious effects in Endo-VEGF animals. Pregnancies surviving to GD16 exhibited (M) excessive vaginal bleeding and (N-P) termination of pregnancy or resorption (arrows denote resorption sites) as well as (Q) widespread and extensive hemorrhaging in fetuses and placentas (arrowheads) and in deciduas at the maternal-fetal junction (asterisk). Histological examination (R-T) revealed widespread dilation and congestion of maternal blood sinuses (arrowheads) in the labyrinth, venous sinuses, and veins at maternal-fetal junctions, and MSB staining (U and V) demonstrated extensive fibrin extravasation (arrows) in the labyrinth and at the maternal-fetal junction. Results are mean ± SD. *P < 0.05 (n = 15). Scale bars: 2 mm (A-D); 500 μm (E, F, and R); 50 μm (G-J); 100 μm (S-V).

Although an infection with Entamoeba histolytica is most commonly asymptomatic, the potential for invasive, metastatic disease, coupled with its high prevalence, makes amoebiasis a major health problem throughout much of the world. Most amoebiasis-related mortality stems from extra-intestinal infection. In these cases, trophozoites penetrate the epithelial layer and lamina propria of the bowel mucosa, enter the bloodstream, and then disseminate to almost any organ or tissue, most commonly the liver.The mechanisms that allow tissue penetration are not well understood. Ultrastructural and histopathological studies (reviewed in reference 1) have shown that, during invasion of the bowel wall, trophozoites are seen at the margin of ulcerative lesions adjacent to healthy tissue. Degeneration of epithelial cells adjacent to invading trophozoites and dissolution of the basement membrane of the mucosa have been observed (2-4). These findings suggest that histolytic and proteolytic factors may be elaborated to facilitate mucosal damage and invasion.Two general types of histolytic factors have been proposed: cytotoxic factors which may directly damage cells, such as a secreted "amoebapore" ion channel (5, 6) and proteolytic enzymes, which may attack both cells and extracellular matrix.The virulence ~ of axenically cultured E. histolytica strains has been correlated with the presence of proteolytic enzymes found on the amoeba surface, in secretions, or in extracts of whole trophozoites (9-14). Unfortunately, as none of these proteinases has been purified to homogeneity, important questions remain as to how many are present and how they may contribute to the pathogenesis of amoebiasis.To determine what role secreted proteinases may play in tissue invasion, we assayed the degradation of extracellular matrix by live trophozoites and their secretory products, using an in vitro model of extracellular matrix successfully used to study other invasive parasites (15-18). These studies allowed us to For axenic amoebae in culture, "virulence" is defined in terms of ability to induce lesions in animals (7) or cytopathic effect on cell monolayers (8).

Preeclampsia (PE) is a serious pregnancy complication, affecting about 5–7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks’ gestation and, if left untreated, can lead to serious complications and lifelong disabilities—even death—in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels of vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), are believed to be among the primary pathologies associated with PE. sFlt-1 is produced mainly in the placenta during pregnancy and acts as a decoy receptor, binding to free VEGF (VEGF-A) and placental growth factor (PlGF), resulting in the decreased bioavailability of each to target cells. Despite the pathogenic effects of increased sFlt-1 on the maternal vasculature, recent studies from our laboratory and others have strongly indicated that the increase in sFlt-1 in PE may fulfill critical protective functions in preeclamptic pregnancies. Thus, further studies on the roles of sFlt-1 in normal and preeclamptic pregnancies are warranted for the development of therapeutic strategies targeting VEGF signaling for the treatment of PE. Another impediment to the treatment of PE is the lack of suitable methods for delivery of cargo to placental cells, as PE is believed to be of placental origin and most available therapies for PE adversely impact both the mother and the fetus. The present review discusses the pathogenesis of PE, the complex role of sFlt-1 in maternal disease and fetal protection, and the recently developed placenta-targeted drug delivery system for the potential treatment of PE with candidate therapeutic agents.

Congenital HCMV infection impairs placental development and functions and should be considered as an underlying cause of IUGR, regardless of virus transmission to the fetus.