37 research outputs found
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Neutralizing Monoclonal Antibodies Reduce Human Cytomegalovirus Infection and Spread in Developing Placentas.
Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects worldwide, yet the most effective strategies for preventing virus transmission during pregnancy are unknown. We measured the efficacy of human monoclonal antibodies (mAbs) to HCMV attachment/entry factors glycoprotein B (gB) and the pentameric complex, gH/gL-pUL128-131, in preventing infection and spread of a clinical strain in primary placental cells and explants of developing anchoring villi. A total of 109 explants from five first-trimester placentas were cultured, and infection was analyzed in over 400 cell columns containing ~120,000 cytotrophoblasts (CTBs). mAbs to gB and gH/gL, 3-25 and 3-16, respectively, neutralized infection in stromal fibroblasts and trophoblast progenitor cells. mAbs to pUL128-131 of the pentameric complex, 1-103 and 2-18, neutralized infection of amniotic epithelial cells better than mAbs 3-25 and 3-16 and hyperimmune globulin. Select mAbs neutralized infection of cell column CTBs, with mAb 2-18 most effective, followed by mAb 3-25. Treatment of anchoring villi with mAbs postinfection reduced spread in CTBs and impaired formation of virion assembly compartments, with mAb 2-18 achieving better suppression at lower concentrations. These results predict that antibodies generated by HCMV vaccines or used for passive immunization have the potential to reduce transplacental transmission and congenital disease
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
Human cytomegalovirus (HCMV) is the major viral cause of congenital infection and birth defects. Primary maternal infection often results in virus transmission, and symptomatic babies can have permanent neurological deficiencies and deafness. Congenital infection can also lead to intrauterine growth restriction, a defect in placental transport. HCMV replicates in primary cytotrophoblasts (CTBs), the specialized cells of the placenta, and inhibits differentiation/invasion. Human trophoblast progenitor cells (TBPCs) give rise to the mature cell types of the chorionic villi, CTBs and multi-nucleated syncytiotrophoblasts (STBs). Here we report that TBPCs are fully permissive for pathogenic and attenuated HCMV strains. Studies with a mutant virus lacking a functional pentamer complex (gH/gL/pUL128-131A) showed that virion entry into TBPCs is independent of the pentamer. In addition, infection is blocked by a potent human neutralizing monoclonal antibody (mAb), TRL345, reactive with glycoprotein B (gB), but not mAbs to the pentamer proteins pUL130/pUL131A. Functional studies revealed that neutralization of infection preserved the capacity of TBPCs to differentiate and assemble into trophospheres composed of CTBs and STBs in vitro. Our results indicate that mAbs to gB protect trophoblast progenitors of the placenta and could be included in antibody treatments developed to suppress congenital infection and prevent disease
At Sea Test 2 deployment cruise : cruise 475 on board R/V Oceanus September 22 – 26, 2011 Woods Hole –Woods Hole, MA
The R/V Oceanus, on Cruise 475, carried out the deployment of three moorings for the
Coastal and Global Scale Nodes (CGSN) Implementing Organization of the NSF Ocean
Observatories Initiative. These three moorings are prototypes of the moorings to be used
by CGSN at the Pioneer, Endurance, and Global Arrays. Oceanus departed from Woods
Hole, Massachusetts on September 22, 2011 and steamed south to the location of the
mooring deployments on the shelf break. Over three days, September 23-25, Oceanus
surveyed the bottom at the planned mooring sites, deployed the moorings, and carried out
on site verification of the functioning of the moorings and moored hardware. Oceanus
returned to Woods Hole on September 26, 2011.Funding was provided by the National Science Foundation
through the Consortium for Ocean Leadershi
Zika virus infection of first-trimester human placentas: utility of an explant model of replication to evaluate correlates of immune protection ex vivo.
Cytomegalovirus infection and antibody protection of the developing placenta.
Human cytomegalovirus (HCMV) infection is transmitted from the infected mother to the placenta and fetus. Virus replicates in the decidua, invasive cytotrophoblasts that breach the uterine vasculature and villous cytotrophoblasts underlying syncytiotrophoblasts, then reaches blood vessels in the villus core. Virus replication, fibrosis, and edema result in a hypoxic intrauterine environment and release of cytokines that stimulates compensatory development of the placenta. We employed villous explant cultures to study viral effects on differentiation and test novel approaches to rescue the placenta from infection
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Cytomegalovirus infection and antibody protection of the developing placenta.
Human cytomegalovirus (HCMV) infection is transmitted from the infected mother to the placenta and fetus. Virus replicates in the decidua, invasive cytotrophoblasts that breach the uterine vasculature and villous cytotrophoblasts underlying syncytiotrophoblasts, then reaches blood vessels in the villus core. Virus replication, fibrosis, and edema result in a hypoxic intrauterine environment and release of cytokines that stimulates compensatory development of the placenta. We employed villous explant cultures to study viral effects on differentiation and test novel approaches to rescue the placenta from infection
Cytomegalovirus Infection and Antibody Protection of the Developing Placenta
Human cytomegalovirus (HCMV) infection is transmitted from the infected mother to the placenta and fetus. Virus replicates in the decidua, invasive cytotrophoblasts that breach the uterine vasculature and villous cytotrophoblasts underlying syncytiotrophoblasts, then reaches blood vessels in the villus core. Virus replication, fibrosis, and edema result in a hypoxic intrauterine environment and release of cytokines that stimulates compensatory development of the placenta. We employed villous explant cultures to study viral effects on differentiation and test novel approaches to rescue the placenta from infection
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Survey of cellular immune responses to human cytomegalovirus infection in the microenvironment of the uterine–placental interface
Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, yet there are no established treatments for preventing maternal-fetal transmission. During first trimester, HCMV replicates in basal decidua that functions as a reservoir for virus and source of transmission to the attached placenta and fetal hemiallograft but also contains immune cells, including natural killer cells, macrophages, and T cell subsets, that respond to pathogens, protecting the placenta and fetus. However, the specific cellular and cytokine responses to infection are unknown, nor are the immune correlates of protection that guide development of therapeutic strategies. Here we survey immune cell phenotypes in intact explants of basal decidua infected with a clinical pathogenic HCMV strain ex vivo and identify specific changes occurring in response to infection in the tissue environment. Using 4-color immunofluorescence microscopy, we found that at 3 days postinfection, virus replicates in decidual stromal cells and epithelial cells of endometrial glands. Infected cells and effector memory CD8+ T cells (TEM) in contact with them make IFN-γ. CD8+ TEM cells produce granulysin and cluster at sites of infection in decidua and the epithelium of endometrial glands. Quantification indicated expansion of two immune cell subtypes-CD8+ TEM cells and, to a lesser extent, iNKT cells. Approximately 20% of immune cells were found in pairs in both control and infected decidua, suggesting frequent cross-talk in the microenvironment of decidua. Our findings indicate a complex immune microenvironment in basal decidua and suggest CD8+ TEM cells play a role in early responses to decidual infection in seropositive women
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
Human cytomegalovirus (HCMV) is the major viral cause of congenital infection and birth defects. Primary maternal infection often results in virus transmission, and symptomatic babies can have permanent neurological deficiencies and deafness. Congenital infection can also lead to intrauterine growth restriction, a defect in placental transport. HCMV replicates in primary cytotrophoblasts (CTBs), the specialized cells of the placenta, and inhibits differentiation/invasion. Human trophoblast progenitor cells (TBPCs) give rise to the mature cell types of the chorionic villi, CTBs and multi-nucleated syncytiotrophoblasts (STBs). Here we report that TBPCs are fully permissive for pathogenic and attenuated HCMV strains. Studies with a mutant virus lacking a functional pentamer complex (gH/gL/pUL128-131A) showed that virion entry into TBPCs is independent of the pentamer. In addition, infection is blocked by a potent human neutralizing monoclonal antibody (mAb), TRL345, reactive with glycoprotein B (gB), but not mAbs to the pentamer proteins pUL130/pUL131A. Functional studies revealed that neutralization of infection preserved the capacity of TBPCs to differentiate and assemble into trophospheres composed of CTBs and STBs in vitro. Our results indicate that mAbs to gB protect trophoblast progenitors of the placenta and could be included in antibody treatments developed to suppress congenital infection and prevent disease
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