Shallow invasion by the extravillous trophoblast into the uterine wall reduces placental perfusion and results in placental dysfunction, but the causes of shallow placental invasion are unknown. The hypothesis to be tested is that infection of invasive trophoblast early in gestation by adeno-associated virus (AAV) and other common viruses that help AAV to replicate causes obstetric complications that result from placental dysfunction, including spontaneous miscarriage, fetal growth restriction, and preeclampsia. Previously, AAV was shown to be able to infect undifferentiated and terminally differentiated trophoblast cells. AAV and its helper viruses (i.e., adenovirus, papillomavirus, herpesvirus, and cytomegalovirus) were discovered in trophoblast cells from miscarriages and in amniocytes from women with preterm premature rupture of the membranes. A relationship between placental viral infections and pathologic abnormalities was reported in cases of fetal growth restriction, and AAV DNA was found in placental tissue from cases of preeclampsia (11/35 cases) and spontaneous preterm birth (8/19 cases). Finally, the serum of 90 women during the first trimester of pregnancy was screened for anti-AAV antibodies, and primary AAV infections (the presence of IgM antibodies) were associated with an increased risk of spontaneous miscarriage (P=0.03). In this proposal, case-control studies will be conducted to determine if AAV infection is associated with a spectrum of adverse reproductive outcomes, and in vitro experiments will be performed to test the hypothesis that viral infection induces pathologic lesions which impair placental invasion of the uterine wall.
Three specific aims are proposed: 1) to conduct a case-control study using PCR-based analyses to compare the incidence of placental viral infection and associated pathologic lesions in women whose pregnancies are complicated by fetal growth restriction and/or severe preeclampsia (cases) and controls; 2) to conduct a nested case-control study in which maternal serum during the first trimester of pregnancy is screened for antibodies against AAV and its helper viruses, to correlate early maternal viral infection with adverse outcomes attributed to placental dysfunction; 3) to determine the ability of AAV and helper viruses to infect extravillous trophoblast cell lines in vitro and define the pathologic effects associated with viral infection of these cells and villous explants. These experiments will provide insights into the role of viral infection in the pathogenesis of placental dysfunction.
