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ABSTRACT: We investigated human cytomegalovirus pathogenesis by comparing infection with the low-passage, endotheliotropic strain VR1814 and the attenuated laboratory strain AD169 in human placental villi as explants in vitro and xenografts transplanted into kidney capsules of SCID mice (ie, mice with severe combined immunodeficiency). In this in vivo human placentation model, human cytotrophoblasts invade the renal parenchyma, remodel resident arteries, and induce a robust lymphangiogenic response. VR1814 replicated in villous and cell column cytotrophoblasts and reduced formation of anchoring villi in vitro. In xenografts, infected cytotrophoblasts had a severely diminished capacity to invade and remodel resident arteries. Infiltrating lymphatic endothelial cells proliferated, aggregated, and failed to form lymphatic vessels. In contrast, AD169 grew poorly in cytotrophoblasts in explants, and anchoring villi formed normally in vitro. Likewise, viral replication was impaired in xenografts, and cytotrophoblasts retained invasive capacity, but some partially remodeled blood vessels incorporated lymphatic endothelial cells and were permeable to blood. The expression of both vascular endothelial growth factor (VEGF)-C and basic fibroblast growth factor increased in VR1814-infected explants, whereas VEGF-A and soluble VEGF receptor-3 increased in those infected with AD169. Our results suggest that viral replication and paracrine factors could undermine vascular remodeling and cytotrophoblast-induced lymphangiogenesis, contributing to bleeding, hypoxia, and edema in pregnancies complicated by congenital human cytomegalovirus infection.
American Journal Of Pathology 09/2012; 181(5):1540-59. · 4.89 Impact Factor
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ABSTRACT: Cytomegalovirus (CMV) is the major cause of congenital infection and disease leading to permanent birth defects. In about 35-40% of pregnant women with primary CMV infection, virus crosses the placenta, resulting in the birth of congenitally infected babies. In contrast, this happens in only 1-3% of seropositive women with strong CMV-specific humoral immunity. Whether CMV reaches the fetus and disseminates depends on the level of high-avidity antibodies in the maternal circulation and the passive immunity of the fetus.
To identify CMV infection in uncomplicated deliveries based on detection of viral DNA in placental biopsy specimens at term. To quantify CMV-specific IgG avidity, neutralizing titer, IgG1 concentration, and characterize the immunoblot profiles for CMV proteins in paired samples of placental and cord blood sera.
In accord with earlier reports, CMV DNA was detected in 39% (11/28) of placentas with mean- to high-avidity CMV-specific IgG. In seropositive women, the concentration of antiviral antibodies, specifically IgG1, increased in the fetal bloodstream, and CMV neutralizing titers in maternal and fetal blood were comparable.
CMV-specific, high-avidity neutralizing antibodies from maternal circulation are transcytosed to the fetal bloodstream, contribute to suppression of viral replication in the placenta and could prevent congenital disease.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 10/2009; 46 Suppl 4:S58-63. · 3.12 Impact Factor
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ABSTRACT: Human cytomegalovirus (CMV) infection is a major cause of morbidity in immunosuppressed individuals, and congenital CMV infection is a leading cause of birth defects in newborns. Infection with pathogenic viral strains alters cell-cell and cell-matrix interactions, affecting extracellular matrix remodeling and endothelial cell migration. The multifunctional cytokine transforming growth factor (TGF)-beta1 regulates cell proliferation, differentiation, and extracellular matrix remodeling. Secreted as a latent protein complex, TGF-beta1 requires activation before binding to receptors that phosphorylate intracellular effectors. TGF-beta1 is activated by integrin alphavbeta6, which is strongly induced in the epithelium by injury and inflammation but has not previously been found in endothelial cells. Here, we report that CMV infection induces integrin alphavbeta6 expression in endothelial cells, leading to activation of TGF-beta1, signaling through its receptor ALK5, and phosphorylation of its intracellular effector Smad3. Infection of endothelial cells was also found to stimulate collagen synthesis through a mechanism dependent on both TGF-beta1 and integrin alphavbeta6. Immunohistochemical analysis showed integrin alphavbeta6 up-regulation in capillaries proximal to foci of CMV infection in lungs, salivary glands, uterine decidua, and injured chorionic villi of the placenta, demonstrating both its induction in endothelium and up-regulation in epithelium in vivo. Our results suggest that activation of TGF-beta1 by integrin alphavbeta6 contributes to pathological changes and may impair endothelial cell functions in tissues that are chronically infected with CMV.
American Journal Of Pathology 05/2008; 172(4):1127-40. · 4.89 Impact Factor
