The Mechanisms of Placental Viral Infection

Abstract

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.

Developmental Regulation of Human Cytomegalovirus Receptors in Cytotrophoblasts Correlates with Distinct Replication Sites in the Placenta

“…Syncytiotrophoblasts do not express the coxsackievirus and adenovirus receptor and are resistant to adenovirus entry (29). Cytotrophoblasts in floating villi express this receptor in early gestation but not at later times; receptor-expressing extravillous cytotrophoblasts are easily infected in vitro.…”

Cytomegalovirus Infection of Human Syncytiotrophoblast Cells Strongly Interferes with Expression of Genes Involved in Placental Differentiation and Tissue Integrity

“…Although there is extensive evidence that CMV-related pathology is caused by direct infection of the fetus in utero, recent work has also highlighted the importance of the role of direct viral infection of the placenta in the pathogenesis of congenital CMV infection (5,6). There is evidence that the route of transmission of CMV to the fetus is via the placenta, which is seeded as a consequence of maternal viremia (5,6).…”

“…There is evidence that the route of transmission of CMV to the fetus is via the placenta, which is seeded as a consequence of maternal viremia (5,6). In addition to serving as a gateway to the fetus, the placenta may be directly injured by CMV, conceivably leading to intrauterine growth retardation and fetal disease (7)(8)(9)(10).…”

Role of placenta in the vertical transmission of human immunodeficiency virus

“…2 The susceptibility of trophoblast cells to infection by other viruses, such as adenovirus and herpes simplex virus, reduces as trophoblasts differentiated into syncytiotrophoblasts due to decreased expression of the viral receptors. 3 Hepatitis B virus transcytosis may occur across the undifferentiated trophoblasts early in pregnancy. 4 In HIV-1-infected mothers with no protective antiretroviral therapy during pregnancy, trophoblasts have the viral sequences.…”