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(Fisher et al. 2000; Yamamoto-Tabata et al. 2004). Invasiveness of infected cytotro-
phoblasts and cell aggregates was dramatically impaired. In addition, CMV exploits
the similarity between viral and human IL-10 to impair the cells' invasion functions
as a consequence of reduced proteinase activity. Cytotrophoblast invasiveness was
impaired by treatment with human IL-10 or cmvIL-10 in accord with decreased
MMP-9 production and activity. These results showed that cmvIL-10, like human
IL-10, impairs cytotrophoblast invasiveness indirectly by impairing MMP-9 activity.
The effect was greater than what could be accounted for by the number of infected
cytotrophoblasts, suggesting that secreted viral and/or cellular factors could
affect uninfected cells in the aggregates and influence the behavior of the population
as a whole.
Implications for Congenital CMV Infection
Recent gene expression profiling of conjoined areas of the human placenta and
decidua that compose the maternal-fetal interface revealed dramatic changes
between midgestation and term (Winn et al. 2007). Many of the developmentally
expressed genes are known in other contexts to be involved in differentiation,
motility, transcription, immunity, angiogenesis and extracellular matrix modula-
tion. We recently examined placentas from pregnancies complicated by sympto-
matic congenital infection and fetal intrauterine growth restriction (Nigro et al.
1999, 2005). Although sites of viral replication were rare, fibrinoid deposition
and necrosis resulting from viral damage in the placenta and markedly reduced
cytotrophoblast invasion in decidua were evident as compared with uninfected
healthy controls (E. Maidji, G. Nigro, S. Muci and L. Pereira, unpublished obser-
vations). Moreover, expression of genes associated with inflammatory responses,
oxidative stress, chemotaxis, extracellular matrix deposition and angiogenesis
was broadly dysregulated. These results suggest that early gestation intrauterine
infection alters the local environment directly and through paracrine mechanisms,
with long-term effects that could result in placental insufficiency as gestation
progresses. Low birth weight is associated with increased rates of cardiovascular
disease and non-insulin-dependent diabetes in adult life (Lau and Rogers 2004;
Reyes and Manalich 2005). The fetal origins hypothesis proposes that these
diseases originate through fetal adaptation - cardiovascular, metabolic or endocrine
in nature - made when the fetus is undernourished (Barker 1999). A better under-
standing of the molecular mechanisms underlying placental dysfunction could
allow formulation of novel treatment for congenital infection, of benefit to
women with pregnancy disorders and fetal intrauterine growth restriction (Cetin
et al. 2004).
Acknowledgements
These studies were supported by grants from the National Institutes of
Health (AI46657, AI53782) and the Thrasher Research Fund 02821-7 and from the Academic
Senate of the University of California, San Francisco.
