At the uterine-placental interface, fetal cytotrophoblasts invade the decidua, breach maternal blood vessels, and form heterotypic contacts with uterine microvascular endothelial cells. In early gestation, differentiatinginvading cytotrophoblasts produce high levels of matrix metalloproteinase 9 (MMP-9), which degrades the extracellular matrix and increases the invasion depth. By midgestation, when invasion is complete, MMP levels are reduced. Cytotrophoblasts also produce human interleukin-10 (hIL-10), a pleiotropic cytokine that modulates immune responses, helping to protect the fetal hemiallograft from rejection. Human cytomegalovirus (CMV) is often detected at the uterine-placental interface. CMV infection impairs cytotrophoblast differentiation and invasion, altering the expression of the cell adhesion and immune molecules. Here we report that infection with a clinical CMV strain, VR1814, but not a laboratory strain, AD169, downregulates MMP activity in uterine microvascular endothelial cells and differentiating-invading cytotrophoblasts. Infected cytotrophoblasts expressed CMV IL-10 (cmvIL-10) mRNA and secreted the viral cytokine, which upregulated hIL-10. Functional analyses showed that cmvIL-10 treatment impaired migration in endothelial cell wounding assays and cytotrophoblast invasion of Matrigel in vitro. Comparable changes occurred in cells that were exposed to recombinant hIL-10 or cmvIL-10. Our results show that cmvIL-10 decreases MMP activity and dysregulates the cell-cell and/or cell-matrix interactions of infected cytotrophoblasts and endothelial cells. Reduced MMP activity early in placental development could impair cytotrophoblast remodeling of the uterine vasculature and eventually restrict fetal growth in affected pregnancies.

We studied the incidence of pathogenic bacteria and concurrent infections with human cytomegalovirus (CMV) and herpes simplex virus (HSV) type 1 and 2 in biopsy samples from the placenta and decidua of women with healthy pregnancies. By polymerase chain reaction analysis, we found that 38% of placental samples were positive for selected bacteria and viruses. CMV, HSV-1, and HSV-2 were detected in isolation or with bacteria in first- and second-trimester samples. Certain bacteria were detected more often during the second trimester than during the first--Ureaplasma urealyticum, Mycoplasma hominis, and Gardnerella/Bifidobacterium species. In paired samples from first-trimester tissues, the detection rate for viruses, compared with most bacteria, was higher in the decidua than in the adjacent placenta. In contrast, bacteria were more frequently detected in placenta. Analyses of immunoglobulin G isolated from the placenta support the hypothesis that immune responses suppress CMV reactivation in the presence of pathogenic bacteria at the maternal-fetal interface.

Cytomegalovirus (CMV), the major viral cause of congenital disease, infects the uterus and developing placenta and spreads to the fetus throughout gestation. Virus replicates in invasive cytotrophoblasts in the decidua, and maternal immunoglobulin G (IgG)-CMV virion complexes, which are transcytosed by the neonatal Fc receptor across syncytiotrophoblasts, infect underlying cytotrophoblasts in chorionic villi. Immunity is central to protection of the placenta-fetal unit: infection can occur when IgG has a low neutralizing titer. Here we used immunohistochemical and function-blocking methods to correlate infection in the placenta with expression of potential CMV receptors in situ and in vitro. In placental villi, syncytiotrophoblasts express the virion receptor epidermal growth factor receptor (EGFR) but lack integrin coreceptors, and virion uptake occurs without replication. Focal infection can occur when transcytosed virions reach EGFR-expressing cytotrophoblasts that selectively initiate expression of ␣V integrin. In cell columns, proximal cytotrophoblasts lack receptors and distal cells express integrins ␣1␤1 and ␣V␤3, enabling virion attachment. In the decidua, invasive cytotrophoblasts expressing coreceptors upregulate EGFR, thereby dramatically increasing susceptibility to infection. Our findings indicate that virion interactions with cytotrophoblasts expressing receptors in the placenta (i) change as the cells differentiate and (ii) correlate with spatially distinct sites of CMV replication in maternal and fetal compartments.Human cytomegalovirus (CMV) is the leading cause of congenital viral infection in children, with an incidence in the United States of about 1 to 3% of live births. Primary CMV infection during gestation poses a 40 to 50% risk of intrauterine transmission (5), whereas reactivated infection in seropositive women rarely causes symptomatic disease, highlighting the role of immunity in fetal protection (16). Symptomatic infants have intrauterine growth restriction, and most survivors (28%) have permanent sequelae, including neurological defects, mental retardation, retinopathy, and sensorineuronal deafness (12). Although virus transmission can occur throughout pregnancy, congenital disease is more severe when primary infection takes place during early gestation (54). Intrauterine growth restriction and loss of the fetus without virus transmission, which are associated with congenital CMV infection, originate in placental pathology (3,21).Placentation is a stepwise process whereby specialized cytotrophoblast progenitor cells leave the basement membrane to initiate blood flow, differentiating along two pathways depending on their location (Fig. 1). In floating villi, cells fuse to form a multinucleate syncytial covering attached at one end to the tree-like fetal portion of the placenta. Covered by syncytiotrophoblasts, these villi float in a stream of maternal blood, a source of nutrients and immunoglobulin G (IgG) transported to the fetus. In anchoring villi, cytotrophoblasts switch from an ...

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