The mechanisms of placental viral infection.

The placenta is a dynamic organ whose structure and function change throughout pregnancy. There is compelling evidence that the placenta plays an integral role in the vertical transmission of viruses, such as cytomegalovirus and human immunodeficiency virus, from the mother to the fetus. Although the sequelae of congenital viral infection (i.e., fetal anomalies, intrauterine fetal death, and persistent postnatal infection) may be devastating, very little is known about the passage of viruses across the placenta and the pathologic consequences of placental viral infection. We postulate that the syncytiotrophoblast, which forms a continuous barrier between the maternal and fetal circulation, is relatively resistant to viral infection. In support of this hypothesis, we observed that the susceptibility of trophoblast cells to infection by adenovirus and herpes simplex virus and the expression of viral receptors were reduced as trophoblast cells terminally differentiated into syncytiotrophoblast. Conversely, we observed that undifferentiated, extravillous trophoblast cells, which are susceptible to adenovirus infection, underwent pathologic changes (i.e., apoptosis) when infected by adenovirus in the presence of decidual lymphocytes (which were used to simulate the maternal immune response to viral infection). Based on these findings, we speculate that viral infection of extravillous trophoblast cells may negatively impact the process of placental invasion and predispose the mother and fetus to adverse reproductive outcomes that result from placental dysfunction.

Differential expression of the coxsackievirus and adenovirus receptor regulates adenovirus infection of the placenta.

The molecular mechanisms and pathologic significance of placental viral infections are poorly understood. We investigated factors that regulate placental infection by adenovirus, which is the most common viral pathogen identified in fetal samples from abnormal pregnancies (i.e., fetal growth restriction, oligohydramnios, and nonimmune fetal hydrops). We also determined the pathologic significance of placental adenovirus infection. Northern hybridization, flow cytometry, and immunostaining revealed that placental expression of the coxsackievirus and adenovirus receptor (CAR) varied with gestational age and trophoblast phenotype. The CAR was continuously expressed in invasive or extravillous trophoblast cells but not in villous trophoblast cells. We postulate that the villous syncytiotrophoblast, which does not express CAR and is resistant to adenovirus infection, limits the transplacental transmission of viral pathogens, including adenovirus. Conversely, extravillous trophoblast cells underwent apoptosis when infected by adenovirus in the presence of decidual lymphocytes (which simulated the maternal immune response to viral infection). Thus, adenovirus infection and/or the maternal immune response to adenovirus infection induced the death of placental cell types that expressed CAR. Consequently, we speculate that adenovirus infection of extra-villous trophoblast cells may negatively impact the process of placental invasion and predispose the mother and fetus to adverse reproductive outcomes that result from placental dysfunction.

Transplacental drug delivery: gene and virus delivery to the trophoblast.

The development of successful strategies for delivering genes to the placenta may provide new opportunities for modifying trophoblast function in order to learn more about trophoblast physiology and to offer novel therapeutic options for complications of pregnancy that result from placental dysfunction. Replication-deficient recombinant viral vectors are useful vehicles for introducing genes into cells in vitro and in vivo. Recombinant adenovirus and herpes simplex virus vectors are unable to efficiently infect and transduce terminally differentiated trophoblastic cells. However, recombinant adeno-associated virus vectors transduce terminally differentiated trophoblastic cells, and a Sindbis virus construct efficiently transduces and destroys trophoblastic cancer cells. We describe the features that make particular viral vectors attractive for gene transfer to trophoblastic cells.