Human cytomegalovirus (CMV) is the leading viral cause of birth defects in the United States. Prenatal infection occurs in 1-3% of births and can lead to intrauterine growth restriction and permanent birth defects, including mental retardation, neurological defects, and deafness. Temporary symptoms of congenital disease can result from lack of nutrient and oxygen transport to the fetus caused by impaired placental development and function. In vitro studies from our group have shown that this impairment results from poor invasion of the uterine wall by cytotrophoblasts (CTBs) and focal changes in uterine vascular remodeling. CMV-infected placental cells alter their expression of molecules required for invasion, migration, and cell-cell and cell-matrix adhesion. Our recent work has revealed that CMV infection alters the expression of proteins associated with hypoxia-inducible angiogenic factors. Importantly, a physiological balance between pro- and anti-angiogenic factors control placental development and an alteration of this balance directly impairs cell differentiation/ invasion. CTBs express one of these regulators during invasion-carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-a member of the immunoglobulin superfamily. CEACAM1 acts as an effector of vascular endothelial growth factor during angiogenesis and its expression is upregulated in response to hypoxia. Interestingly, a soluble form of CEACAM1 (sCEACAM1) produced by CEACAM1- expressing cells inhibits angiogenesis in vitro and in vivo. Our studies have shown that CMV infection induces CEACAM1 in neighboring, uninfected endothelial cells, but not in infected cells, through a paracrine effect driven by viral infection. Increased secretion of CEACAM1 from CMV-infected cell cultures and recombinant sCEACAM1 severely impair endothelial cell migration, a key step in angiogenesis. Our central hypothesis is that sCEACAM1 is an important paracrine mediator of viral pathogenesis through its inhibition of local angiogenesis and/or CTB differentiation/invasion. Importantly, CMV infection induces the expression of multiple CEACAM1 isoforms, which are likely glycosylated and secreted. The effect of CEACAM1 function might depend on a combination of isoforms with varying ratios, presence or absence or sCEACAM1 and the nature of various glycoforms. The goal of the current proposal is to determine the specific functions of multiple sCEACAM1 isoforms from CMV- infected specialized cells from the uterine- placental interface. Accordingly, we propose the following Specific Aims:
Aim 1. Determine the effects of sCEACAM1 from CMV-infected endothelial cells on angiogenesis.
Aim 2. Determine the role of CEACAM1 in controlling CTB differentiation and invasion. Studies in this application seek to identify the underlying molecular processes dysregulated in angiogenesis and vascular remodeling in congenitally infected placentas, and increase our understanding of the molecular mechanisms that undermine development and could have broad clinical application to vascular biology.

Public Health Relevance

Congenital cytomegalovirus (CMV) infection is the leading viral cause of birth defects in the United States. Primary infection in pregnant women frequently leads to birth defects including neurological disorders and deafness. This project addresses molecular mechanisms of viral damage that impairs functions of the human placenta and could identify novel proteins with clinical importance for development of diagnostic and therapeutic strategies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Pregnancy and Neonatology Study Section (PN)
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Reddy, Uma M
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University of California San Francisco
Anatomy/Cell Biology
Schools of Dentistry
San Francisco
United States
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Tabata, Takako; Petitt, Matthew; Fang-Hoover, June et al. (2016) Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta. Am J Pathol 186:2970-2986
Tabata, Takako; Petitt, Matthew; Zydek, Martin et al. (2015) Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta. J Virol 89:5134-47
Pereira, Lenore; Petitt, Matthew; Fong, Alex et al. (2014) Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection. J Infect Dis 209:1573-84
Zydek, Martin; Petitt, Matthew; Fang-Hoover, June et al. (2014) HCMV infection of human trophoblast progenitor cells of the placenta is neutralized by a human monoclonal antibody to glycoprotein B and not by antibodies to the pentamer complex. Viruses 6:1346-64
Pereira, Lenore; Petitt, Matthew; Tabata, Takako (2013) Cytomegalovirus infection and antibody protection of the developing placenta. Clin Infect Dis 57 Suppl 4:S174-7
Tabata, Takako; Petitt, Matthew; Fang-Hoover, June et al. (2012) Cytomegalovirus impairs cytotrophoblast-induced lymphangiogenesis and vascular remodeling in an in vivo human placentation model. Am J Pathol 181:1540-59