Biology Reference
In-Depth Information
Introduction
Primary maternal CMV infection during gestation poses a 40%-50% risk of intrau-
terine transmission (Britt 1999), whereas reactivated infection in seropositive
women rarely causes symptomatic disease, highlighting the central role for maternal
humoral immunity in fetal protection (Fowler et al. 1992, 2003). It has long been
recognized that congenital disease and placental damage are more severe when
primary maternal infection occurs in the first trimester (Stagno et al. 1986; Garcia
et al. 1989; Muhlemann et al. 1992; Benirschke and Kaufmann 2000). Several
groups have reported that cytotrophoblasts, the specialized cells that compose the
developing placenta, support CMV replication in utero (Sinzger et al. 1993; Fisher
et al. 2000; Kumazaki et al. 2002; Pereira et al. 2003; McDonagh et al. 2004;
Trincado et al. 2005). Cells isolated from early gestation (Fisher et al. 2000) and
term placentas (Halwachs-Baumann et al. 1998; Hemmings et al. 1998; Tabata
et al. 2007) are susceptible to CMV infection. Studies in early gestation revealed
that virus replicates in the pregnant uterus and spreads from decidua to the adjacent
placenta (Pereira et al. 2003; McDonagh et al. 2004). Islands of infection are found
in cytotrophoblasts, whereas intercalating macrophages and dendritic cells internalize
virions without replication (Fisher et al. 2000; Pereira et al. 2003; Maidji et al.
2006). In the placenta, infection occurs in small foci of cytotrophoblasts underlying
syncytiotrophoblasts when maternal antibody has low neutralizing titer, but not
high titer. Here we consolidate recent studies designed to clarify the synergy
between the neonatal Fc receptor for IgG in syncytiotrophoblasts and virion
receptors induced by villous cytotrophoblasts and invasive cells in the uterine
interstitium and vasculature. Infection in early gestation could undermine placental
development and lead to complications including fetal intrauterine growth restriction,
a hallmark of congenital infection.
Spatially Distinct Infection in the Developing Placenta
Placentation is a stepwise process whereby specialized cytotrophoblast progenitor
cells leave the basement membrane, differentiating along two pathways depending
on their location (Fig. 1). In floating villi, cells fuse to form a multinucleate syncytial
covering, syncytiotrophoblasts, attached at one end to the tree-like fetal portion of
the placenta. These villi float in a stream of maternal blood, the source of nutrients
and IgG transported by the neonatal Fc receptor for passive immunity of the fetus
(Story et al. 1994; Simister et al. 1996). In anchoring villi, cytotrophoblasts switch
from an epithelial to an endothelial phenotype controlled through the coordinated
actions of numerous interrelated factors (Zhou et al. 1997; Janatpour et al. 2000;
Genbacev et al. 2001). Cytotrophoblasts remodel uterine arteries, replacing
endothelial cells and creating a hybrid vasculature that increases maternal blood
flow to supply the developing placenta (Damsky et al. 1994; Damsky and Fisher
1998). The cells express adhesion molecules - integrins, Ig superfamily members
