Human cytomegalovirus (CMV) infection of the embryo/fetus is the leading cause of congenital viral infection. It occurs in 1 percent of live births in the United States. The consequences include poor neurologic development, visual impairment, and sensorineural hearing loss. Placentas from women with congenital CMV who abort spontaneously (15 percent) show evidence of infection without fetal involvement, indicating that placental infection precedes virus transmission to the fetus. Successful pregnancy depends on normal placental development, a stepwise process that involves differentiation of the organ's epithelial stem cells, termed cytotrophoblasts (CTBs). CTBs differentiate via two pathways into villi that either anchor the placenta to the uterine wall or float in maternal blood. In the first pathway, CTBs in anchoring villi switch on expression of adhesion receptors and proteinases that are needed for invasion of maternal arteries, as well as immune molecules that elicit maternal tolerance. Our studies showed that CMV infection of first trimester differentiating/invading CTBs in vitro downregulates expression of two functionally important stage-specific antigens nonclassical MHC class Ib HLA-G and integrin alpha1beta1. Moreover, the invasion competence of infected CTBs in vitro was dramatically impaired as was the 2invasiveness of CTBs isolated from a placenta infected with CMV in vivo. This correlation between impaired invasion and disregulation of alpha1beta1 suggests that faulty invasion of maternal arteries may be a hallmark of CMV-infected placentas. In the second pathway, CTBs fuse to form syncytiotrophoblasts (STBs) that cover floating villi. When floating villi were exposed to CMV in vitro, STBs were uninfected and the underlying CTB stem cells were infected. This unexpected result suggested that STBs transmit virus from maternal blood, bathing their surface, to the CTB stem cells adjacent to the villus core. Non-neutralizing anti-viral IgG in primary infection may enhance transcytosis of IgG-coated virions. It is hypothesized that CMV is transmitted from the mother to the placenta and the embryo/fetus by infection of CTB stem cells in floating villi, following transcytosis across the STB barrier, and by infection of invasive CTBs within the uterine wall.
The specific aims are: (1) Determine the effects of CMV infection on CTB invasiveness and immune function in vitro and then establish relevance in vivo. 2) Identify/map CMV genes involved in disregulating CTB differentiation/invasion and immune function. (3) Determine whether infection of underlying CTB stem cells near the villus stromal core occurs by transcytosis of IgG-coated CMV virions across the surface layer of STBs in vitro and then establish relevance in vivo. These experiments will advance our knowledge of the role of the placenta in pregnancy complications due to CMV infection, a critical issue in prenatal development. The results could offer the first molecular evidence regarding the route of transmission and lead to strategies to prevent infection of the fetus.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Beisel, Christopher E
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University of California San Francisco
Anatomy/Cell Biology
Schools of Dentistry
San Francisco
United States
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Petitt, Matthew; Tabata, Takako; Puerta-Guardo, Henry et al. (2017) Zika virus infection of first-trimester human placentas: utility of an explant model of replication to evaluate correlates of immune protection ex vivo. Curr Opin Virol 27:48-56
Tabata, Takako; Petitt, Matthew; Puerta-Guardo, Henry et al. (2016) Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission. Cell Host Microbe 20:155-66
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
Kauvar, Lawrence M; Liu, Keyi; Park, Minha et al. (2015) A high-affinity native human antibody neutralizes human cytomegalovirus infection of diverse cell types. Antimicrob Agents Chemother 59:1558-68
Kirchmeier, Marc; Fluckiger, Anne-Catherine; Soare, Catalina et al. (2014) Enveloped virus-like particle expression of human cytomegalovirus glycoprotein B antigen induces antibodies with potent and broad neutralizing activity. Clin Vaccine Immunol 21:174-80
Pereira, Lenore; Petitt, Matthew; Fong, Alex et al. (2014) Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection. J Infect Dis 209:1573-84
McCutcheon, Krista M; Gray, Julia; Chen, Natalie Y et al. (2014) Multiplexed screening of natural humoral immunity identifies antibodies at fine specificity for complex and dynamic viral targets. MAbs 6:460-73
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

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