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with IgG alone, suggesting that virions drive caveolae formation (Maidji et al.
2006). CMV gB accumulates in caveosomes, but nucleocapsids and viral DNA
remain cytoplasmic without replication, suggesting endocytosis of immune com-
plexes in syncytiotrophoblasts.
Clusters of adjacent cytotrophoblasts underlying syncytiotrophoblasts expressed
integrin αV (Fig. 2b). When infection was detected in villous cytotrophoblasts, as
indicated by the nuclear (green) staining pattern, the cells stained intensely for
EGFR (Fig. 2c). Notably, integrin α1β1 was absent (not shown), which confirms
earlier reports (Damsky et al. 1992; Zhou et al. 1997). Double immunostaining
showed that Toledo rec replicated in cytotrophoblasts that expressed both integrin
αV (red) and EGFR (blue) (Fig. 2d). Together these results indicated that CMV
virions internalize in syncytiotrophoblasts with EGFR alone. Inasmuch as more
than half of the population was immune to CMV, and neutralizing antibodies are
secreted into conditioned medium from villus explants (Maidji et al. 2006), viral
replication occurred infrequently (seven of 42 placentas). When placentas con-
tained IgG-CMV virion complexes with low-avidity antibodies, focal replication
occurred in susceptible cytotrophoblast progenitor cells that expressed both EGFR
and integrin αV, providing an explanation for earlier observations (Fisher et al.
2000; Pereira et al. 2003). Likewise, flow cytometric analysis of cytotrophoblasts
isolated from placentas at term confirmed that EGFR and selected integrins were
expressed (Tabata et al. 2007).
Villous cytotrophoblasts express integrin αV but not the β3 subunit, suggesting that
other partners could function as coreceptors, particularly subunits β5 and β6 (Zhou
et al. 1997; Tabata et al. 2007). CMV infection in epithelial-like progenitor cells could
resemble foot-and-mouth disease virus, which binds integrins αVβ3 (Berinstein et al.
1995) and αVβ6 in epithelia (Jackson et al. 2000). We recently observed integrin αVβ6
expression in cytotrophoblasts of floating villi contiguous with large deposits of extra-
cellular matrix (Tabata et al., unpublished observations) and integrin β6 was expressed
in freshly isolated villous cytotrophoblasts of placentas at term (Tabata et al. 2007).
Particular expression of FcRn, endocytosis of immune complexes, coupled with tem-
poral and spatial regulation of virion receptors as cytotrophoblasts differentiate, could
limit virus access to the villous core . These findings help explain the discrepancies
between frequent detection of viral DNA in the decidua (80%), reduced levels in the
placenta (60%), and a low rate of congenital infection in seropositive women (1%-3%)
(Fowler et al. 2003; McDonagh et al. 2004; 2006).
Cell Column Cytotrophoblasts Induce Integrin α1β1 Expression
When early gestation biopsy specimens were stained for potential CMV receptors,
proximal cell columns did not express EGFR, but punctate staining for gB was
sometimes detected at the cell surface, suggesting that virions were clustered in
membranes (Maidji et al. 2007). CMV receptors expressed on cytotrophoblasts in
villus explants were studied in model cell columns of anchoring villi infected with
Toledo rec ex vivo (Fig. 3a). Like cell columns in intact placentas, extravillous
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