Mother

Fig. 1 Diagram of the placental (fetal)-decidual (maternal) interface near the end of the first trimester of human pregnancy (10 weeks of gestational age). A longitudinal section includes floating and anchoring chorionic villi. The floating villus (FV) is bathed by maternal blood. The anchoring villus (AV) functions as a bridge between the fetal and maternal compartments. Cytotrophoblasts in AV form cell columns that attach to the uterine wall. They invade the decidua and uterine vasculature, anchoring the placenta and gaining access to the maternal circulation. Colors illustrate different cell types: syncytiotrophoblasts (ST) (beige), cytotrophoblast (CTB) progenitors and invasive cells (l ight green) , decidual cells (green) , endothelial cells (yellow) , smooth muscle cells (brown), glandular epithelial cells (gray), macrophage/dendritic cells (Mf/DC) (lightpurple/pink), polymorphonuclear neutrophils (PMN) (red), and natural killer cells (NK) (fuchsia)

Fig. 1 Diagram of the placental (fetal)-decidual (maternal) interface near the end of the first trimester of human pregnancy (10 weeks of gestational age). A longitudinal section includes floating and anchoring chorionic villi. The floating villus (FV) is bathed by maternal blood. The anchoring villus (AV) functions as a bridge between the fetal and maternal compartments. Cytotrophoblasts in AV form cell columns that attach to the uterine wall. They invade the decidua and uterine vasculature, anchoring the placenta and gaining access to the maternal circulation. Colors illustrate different cell types: syncytiotrophoblasts (ST) (beige), cytotrophoblast (CTB) progenitors and invasive cells (l ight green) , decidual cells (green) , endothelial cells (yellow) , smooth muscle cells (brown), glandular epithelial cells (gray), macrophage/dendritic cells (Mf/DC) (lightpurple/pink), polymorphonuclear neutrophils (PMN) (red), and natural killer cells (NK) (fuchsia)

and proteinases that enable invasiveness - and immune-modulating factors for maternal tolerance of the hemiallogeneic fetus (Cross et al. 1994; Damsky and Fisher 1998; Norwitz et al. 2001). Villous cytotrophoblasts express certain integrin subunits (Zhou et al. 1997), and interstitial invasive cells upregulate integrin a1p1 expression (Damsky et al. 1994). Endovascular cytotrophoblasts express aVp3 and vasculogenic factors and receptors that mimic the surface of vascular cells (Zhou et al. 1997; Damsky and Fisher 1998). Invasive cytotrophoblasts also upregulate matrix metalloproteinase 9 (MMP-9), which degrades the extracellular matrix of the uterine stroma (Librach et al. 1991), and interleukin 10 (IL-10) for immune tolerance and modulation of metalloproteinases and invasiveness (Roth et al. 1996; Roth and Fisher 1999).

CMV is especially adapted to replicate in the immune tolerant microenvironment at the maternal-fetal interface (Pereira et al. 2005). Examination of intrauterine CMV infection in early gestation revealed patterns of virus replication in the decidua, mirrored in the placenta, and dependent in part on maternal immune responses (Fisher et al. 2000; Pereira et al. 2003; Maidji et al. 2006). With low neutralizing antibody titers, areas of infection are found in the decidua and adjacent placenta. With moderate neutralizing titers, cytotrophoblast infection is reduced in the decidua, and occasional focal infection is found in floating villi. With high neutralizing titers, few cytotrophoblasts contain viral replication proteins in the decidua, and none stain in the placenta. In syncytiotrophoblasts, the neonatal Fc receptor transcytoses complexes of IgG and virions that potentially infect underlying cytotro-phoblasts (Maidji et al. 2006). Consistent patterns of replication in cytotrophoblast progenitors in villi and invasive cells in the decidua suggest that virion receptors are regulated during development.

Human fibroblasts that support CMV replication express the epidermal growth factor receptor (EGFR) (Wang et al. 2003) and co-receptors such as integrins aVp3, a2pi and a6pi (Feire et al. 2004; Wang et al. 2005). In human umbilical vein endothelial cells (HUVEC), outcomes of infection differ depending on EGFR expression levels (E. Huang, personal communication). Coordinated signals from high-level EGFR expression and integrin aVp3 result in rapid delivery of virion capsids to the nucleus. Internalization and nuclear transport involve caveolin-mediated endosomal pathways that are pH independent. Productive infection entails the inhibition of cofilin phosphorylation and increased tubulin acetylation, which are hallmarks of actin disassembly and microtubule assembly. Detailed analysis of naturally infected placentas support strong expression of EGFR and induction of specific integrins as developmentally induced CMV receptors in cytotrophoblasts that enable intrauterine replication in sites optimal for virus amplification and fetal transmission.

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