Biology Reference
In-Depth Information
More recent findings have demonstrated that membrane-bound forms but not
secreted HLA-G can be degraded by US2 (Barel et al. 2003). Decidual NK cells
with cytotoxic activity have been described as well as inhibition of their activity
by soluble HLA-G (Poehlmann et al. 2006; Tabiasco et al. 2006). These findings
point to a complex and dynamic immunological relationship between host, tro-
phoblast and virus, and suggest that understanding the role of the placental effector
functions could lead to further understanding of how HCMV is transmitted to the
developing fetus. Potential routes of transmission to the fetus has been studied in
vivo in the guinea pig model of congenital CMV infection (Griffith et al. 1985,
1986). The finding that maternal viremia can be correlated with intrauterine
transmission and that passively administered virus neutralizing antibodies could
reduce placental infection and intrauterine transmission is consistent with con-
ventional routes of fetal infection (Bourne et al. 2001; Chatterjee et al. 2001). In
this model, placental infection has been correlated with both maternal disease and
fetal wastage associated with placental infiltration with mononuclear cells
(Harrison and Myers 1990; Harrison and Caruso 2000). Thus local inflammatory
response secondary to virus infection can occur at the uterine-placental interface,
arguing that either viral immune evasion functions or an ineffective host immune
response could tip the balance toward fetal infection. Alternatively, the severity
of maternal disease seen in the guinea pig model of congenital CMV infection
also has raised the very distinct possibility that commonly observed disease mani-
festations in the guinea pig pup, such as runting, could be related to placental
inflammation and insufficiency rather than a direct effect of virus infection on the
developing fetal guinea pig. Similar studies have not been accomplished in the
mouse model, presumably because of the multilayered structure of the murine
placenta limits transplacental transfer of MCMV. Currently, rhesus CMV-free
rhesus macaque colonies are being generated and these animals should provide an
ideal experimental animal model for investigation of this human infection. Several
key questions critical to the pathogenesis of congenital CMV infections remain
unanswered, including:
1. What is the relationship between maternal viremia and seeding of the uterus?
2. Is seeding of the placenta associated with cell-free or cell-associated virus?
3. Can resident immune effector functions limit virus infection of the placenta or
are circulating mononuclear cells required?
4. Can ascending infections from the uterine cervix infect the fetus?
5. What is the importance of placental inflammation and fetal outcome?
6. How does preexisting maternal immunity limit transmission?
This last question is important for the design of vaccines to limit damaging
congenital HCMV infections.
Once the virus has entered the fetal circulation, it can in some instances replicate
to high levels and damage a variety of organ systems presumably by lytic replica-
tion, although this has not been experimentally verified. Target organs most com-
monly damaged by severe intrauterine infection include the hepatobiliary system,
the central nervous system, the lungs, and hematopoietic system (Becroft 1981;
