Human Cytomegalovirus-Induced Inhibition of Cytotrophoblast Invasion

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DESCRIPTION (provided by applicant): Significant morbidity and mortality is associated with symptomatic congenital infection with the herpes virus human cytomegalovirus (HCMV). Fifteen percent of women with primary HCMV infection spontaneously abort during early pregnancy; and it is the placenta, not the embryo or fetus that shows evidence of infection. Pathological consequences of placental HCMV infection, including first trimester pregnancy loss, intrauterine growth restriction, pre-eclampsia and preterm labor, are believed to be mediated by the inability of extravillous cytotrophoblasts (EVT) to adequately invade the uterine wall during early first trimester pregnancy resulting in impaired remodeling of maternal spiral arteries and shallow placentation. Preliminary studies demonstrate that HCMV infection of first trimester EVT results in inhibition of EVT invasion and in significant reduction of expression and activity of invasion-promoting matrix metalloproteinase (MMP)-2 and MMP-9. HCMV-induced inhibition of EVT occurs along with increased expression of transforming growth factor (TGF)-21, a factor known to inhibit EVT invasion. Since EVT invasion occurs during first trimester pregnancy when the fetal side of the placental environment is relatively hypoxic and since hypoxia, in other systems, is capable of activating herpesvirus gene expression and lytic replication, low oxygen partial pressure during placentation may actually augment the ability of HCMV to inhibit EVT invasion. To determine the molecular mechanism(s) by which HCMV inhibits EVT invasion, which is the broad, long-term objective of the studies proposed herein, a novel, biologically relevant model of EVT invasion has been developed using bioreactor tissue engineering technology. The hypotheses of the studies proposed are that that HCMV, and more specifically, the viral envelope glycoprotein B (gB) and/or immediate- early gene products, IE1-72 and IE2-86, inhibit EVT invasion during placentation through activation of TGF-21 and modulation of MMP activity; and further, that hypoxia increases the ability of HCMV to inhibit EVT invasion through upregulation of HCMV IE expression and lytic replication. The Specific Aims to test these hypotheses are (1) to determine whether the inhibition of invasion of cultured EVT by HCMV is mediated by early events in the HCMV replication cycle (2) to determine whether HCMV represses invasion- promoting MMP-2, MMP-3, MMP-9 and uPA, and upregulates invasion-repressing TIMP-1, TIMP-2 and PAI-1 in cultured EVT and whether HCMV inhibits the invasiveness of cultured EVT through activation of TGF-21 and (3) to determine whether the relatively hypoxic atmosphere encountered by differentiating CTB during first trimester pregnancy enhances HCMV-induced inhibition of interstitial and endovascular invasion by EVT through increased lytic HCMV replication. Elucidating mechanisms by which HCMV impairs placentation may be key to understanding fetal and maternal pathologies associated with intrauterine HCMV infection. PUBLIC HEALTH RELEVANCE: Fifteen percent of women with primary human cytomegalovirus (HCMV) infection spontaneously abort during early pregnancy, and it is the placenta, not the embryo or fetus, that shows evidence of infection. Additionally, HCMV infection may cause premature delivery, intrauterine growth restriction or pre-eclampsia, all of which are associated with placental pathology. These complications are believed to be, at least in part, the result of inadequate extravillous cytotrophoblast invasion (EVT) of the uterine wall and impaired remodeling of the maternal spiral arteries during early stages of placental development. Defining how HCMV impairs EVT invasion is of major importance to the reproductive community and may provide additional therapeutic targets to maintain viable pregnancy.