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1.
J Virol ; 81(9): 4701-12, 2007 May.
Article in English | MEDLINE | ID: mdl-17314173

ABSTRACT

Cytomegalovirus (CMV), the major viral cause of congenital disease, infects the uterus and developing placenta and spreads to the fetus throughout gestation. Virus replicates in invasive cytotrophoblasts in the decidua, and maternal immunoglobulin G (IgG)-CMV virion complexes, which are transcytosed by the neonatal Fc receptor across syncytiotrophoblasts, infect underlying cytotrophoblasts in chorionic villi. Immunity is central to protection of the placenta-fetal unit: infection can occur when IgG has a low neutralizing titer. Here we used immunohistochemical and function-blocking methods to correlate infection in the placenta with expression of potential CMV receptors in situ and in vitro. In placental villi, syncytiotrophoblasts express the virion receptor epidermal growth factor receptor (EGFR) but lack integrin coreceptors, and virion uptake occurs without replication. Focal infection can occur when transcytosed virions reach EGFR-expressing cytotrophoblasts that selectively initiate expression of alphaV integrin. In cell columns, proximal cytotrophoblasts lack receptors and distal cells express integrins alpha1beta1 and alphaVbeta3, enabling virion attachment. In the decidua, invasive cytotrophoblasts expressing coreceptors upregulate EGFR, thereby dramatically increasing susceptibility to infection. Our findings indicate that virion interactions with cytotrophoblasts expressing receptors in the placenta (i) change as the cells differentiate and (ii) correlate with spatially distinct sites of CMV replication in maternal and fetal compartments.


Subject(s)
Cytomegalovirus Infections/metabolism , Gene Expression Regulation , Placenta/cytology , Receptors, Virus/metabolism , Trophoblasts/metabolism , Virus Replication/physiology , ErbB Receptors/metabolism , Female , Humans , Immunohistochemistry , Integrins/metabolism , Microscopy, Fluorescence , Pregnancy , Trophoblasts/virology , Virus Attachment
2.
J Clin Virol ; 35(2): 210-5, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16386950

ABSTRACT

BACKGROUND: Primary maternal CMV infection is the major risk factor for symptomatic congenital infection as maternal immunity reduces the risk of transmission to the fetus. Analysis of first trimester placentas showed that virus replicates in the uterus and is transmitted to the placenta causing focal infection. OBJECTIVES AND STUDY DESIGN: We examined 78 term placentas from uncomplicated deliveries for the presence of CMV DNA and evaluated evidence of infection by means of immunohistological and serological analysis. RESULTS: PCR analysis of villus biopsy samples and decidua showed that CMV DNA was present in 62% of tissues. Seven placentas with neutralizing titers were further examined by immunohistology for expression of viral proteins. In placentas with high levels of CMV DNA, fetal blood vessels in the villus core contained neutrophils with viral replication proteins, and macrophages/dendritic cells with glycoprotein B (gB). Cord blood samples from 1 of 11 placentas contained CMV DNA, an indication of replication in the fetal compartment. In placentas with low levels of viral DNA, macrophage/dendritic cells in the villus core contained CMV gB. This pattern was comparable to that seen in early gestation placentas from women with strong neutralizing antibodies. CONCLUSIONS: The results show CMV replication proteins in focal areas of the placenta, implying virus transmission to the fetal circulation. These preliminary results suggest that the incidence of asymptomatic congenital CMV infection might be higher than currently estimated.


Subject(s)
Cytomegalovirus Infections/physiopathology , Cytomegalovirus/isolation & purification , Infectious Disease Transmission, Vertical , Placenta Diseases/virology , Pregnancy Complications, Infectious , Cytomegalovirus/genetics , Cytomegalovirus Infections/transmission , DNA, Viral/analysis , Female , Humans , Placenta Diseases/pathology , Pregnancy
3.
J Infect Dis ; 190(4): 826-34, 2004 Aug 15.
Article in English | MEDLINE | ID: mdl-15272412

ABSTRACT

We studied the incidence of pathogenic bacteria and concurrent infections with human cytomegalovirus (CMV) and herpes simplex virus (HSV) type 1 and 2 in biopsy samples from the placenta and decidua of women with healthy pregnancies. By polymerase chain reaction analysis, we found that 38% of placental samples were positive for selected bacteria and viruses. CMV, HSV-1, and HSV-2 were detected in isolation or with bacteria in first- and second-trimester samples. Certain bacteria were detected more often during the second trimester than during the first--Ureaplasma urealyticum, Mycoplasma hominis, and Gardnerella/Bifidobacterium species. In paired samples from first-trimester tissues, the detection rate for viruses, compared with most bacteria, was higher in the decidua than in the adjacent placenta. In contrast, bacteria were more frequently detected in placenta. Analyses of immunoglobulin G isolated from the placenta support the hypothesis that immune responses suppress CMV reactivation in the presence of pathogenic bacteria at the maternal-fetal interface.


Subject(s)
Bifidobacterium/isolation & purification , Cytomegalovirus/isolation & purification , Decidua/microbiology , Gram-Negative Bacteria/isolation & purification , Herpesvirus 1, Human/isolation & purification , Herpesvirus 2, Human/isolation & purification , Placenta/microbiology , Antibodies, Viral/analysis , Bifidobacterium/genetics , Biopsy , Cytomegalovirus/genetics , Cytomegalovirus/immunology , DNA, Bacterial/genetics , DNA, Viral/genetics , Decidua/pathology , Female , Gardnerella/genetics , Gardnerella/isolation & purification , Gram-Negative Bacteria/genetics , Herpesvirus 1, Human/genetics , Herpesvirus 2, Human/genetics , Humans , Immunoglobulin G/analysis , Mycoplasma hominis/genetics , Mycoplasma hominis/isolation & purification , Placenta/immunology , Placenta/pathology , Pregnancy , Pregnancy Trimester, First , Pregnancy Trimester, Second , RNA, Messenger/analysis , Ureaplasma urealyticum/genetics , Ureaplasma urealyticum/isolation & purification
4.
J Virol ; 78(6): 2831-40, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14990702

ABSTRACT

At the uterine-placental interface, fetal cytotrophoblasts invade the decidua, breach maternal blood vessels, and form heterotypic contacts with uterine microvascular endothelial cells. In early gestation, differentiating- invading cytotrophoblasts produce high levels of matrix metalloproteinase 9 (MMP-9), which degrades the extracellular matrix and increases the invasion depth. By midgestation, when invasion is complete, MMP levels are reduced. Cytotrophoblasts also produce human interleukin-10 (hIL-10), a pleiotropic cytokine that modulates immune responses, helping to protect the fetal hemiallograft from rejection. Human cytomegalovirus (CMV) is often detected at the uterine-placental interface. CMV infection impairs cytotrophoblast differentiation and invasion, altering the expression of the cell adhesion and immune molecules. Here we report that infection with a clinical CMV strain, VR1814, but not a laboratory strain, AD169, downregulates MMP activity in uterine microvascular endothelial cells and differentiating-invading cytotrophoblasts. Infected cytotrophoblasts expressed CMV IL-10 (cmvIL-10) mRNA and secreted the viral cytokine, which upregulated hIL-10. Functional analyses showed that cmvIL-10 treatment impaired migration in endothelial cell wounding assays and cytotrophoblast invasion of Matrigel in vitro. Comparable changes occurred in cells that were exposed to recombinant hIL-10 or cmvIL-10. Our results show that cmvIL-10 decreases MMP activity and dysregulates the cell-cell and/or cell-matrix interactions of infected cytotrophoblasts and endothelial cells. Reduced MMP activity early in placental development could impair cytotrophoblast remodeling of the uterine vasculature and eventually restrict fetal growth in affected pregnancies.


Subject(s)
Cytomegalovirus/pathogenicity , Down-Regulation , Endothelial Cells/physiology , Interleukin-10/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Trophoblasts/physiology , Cell Differentiation , Cell Movement , Cytomegalovirus/metabolism , Cytomegalovirus Infections/physiopathology , Cytomegalovirus Infections/virology , Female , Fibroblasts/virology , Humans , Placenta/cytology , Pregnancy , Trophoblasts/virology , Viral Proteins/metabolism
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