Cytomegalovirus Infection of Human Syncytiotrophoblast Cells Strongly Interferes with Expression of Genes Involved in Placental Differentiation and Tissue Integrity

Abstract

ABSTRACT:The principle route of acquisition of cytomegalovirus (CMV) for the fetus is believed to be via the placenta. We subjected purified cytotrophoblast cells obtained from full-term placentas to CMV infection and examined placental gene expression using microarray analyses. Cytotrophoblast cells purified from term placentas differentiated in vitro into a multinucleated syncytium that could be productively infected with CMV, with peak virus titers of approximately 10 4 plaque-forming units (PFU)/mL identified in supernatants at late time points postinoculation. Infected syncytiotrophoblast cells expressed CMV-specific transcripts and proteins, as demonstrated by Northern blot and immunofluorescence assays. Microarray analyses revealed that CMV infection strongly and reproducibly altered trophoblast gene expression, elevating expression of mitotic cell cycle genes, and repressing expression of genes associated with trophoblast differentiation, particularly those associated with formation and stabilization of the extracellular matrix. We conclude that purified, differentiated syncytiotrophoblasts are permissive for CMV replication. Infection of these cells induces significant perturbations in trophoblast transcription. An improved understanding of the molecular events that occur during CMV infection of trophoblasts could provide insights into interventions that might prevent or minimize congenital transmission. (Pediatr Res 61: 565-571, 2007) B irth defects caused by congenital CMV infection represent a major public health problem. Congenital CMV transmission results in substantial long-term neurodevelopmental morbidity in newborns, including mental retardation and sensorineural hearing loss [reviewed in (1)]. While antiviral therapies may limit severity of SNHL, therapeutic invention has limited ability to reverse other neurologic injuries (2). The most effective strategies for control of congenital CMV may require prevention of fetal infection by preconceptual vaccination or anti-CMV immunoglobulins (3,4). However, vaccines and immunoglobulins are not yet licensed for prevention of congenital CMV infection. Therefore, continued study of the molecular pathophysiology of CMV infection in cell types relevant to congenital transmission is warranted, to help facilitate development of novel disease prevention strategies.Although there is extensive evidence that CMV-related pathology is caused by direct infection of the fetus in utero, recent work has also highlighted the importance of the role of direct viral infection of the placenta in the pathogenesis of congenital CMV infection (5,6). There is evidence that the route of transmission of CMV to the fetus is via the placenta, which is seeded as a consequence of maternal viremia (5,6). In addition to serving as a gateway to the fetus, the placenta may be directly injured by CMV, conceivably leading to intrauterine growth retardation and fetal disease (7-10). Thus, study of CMV placental infection may facilitate improved understanding of these potentially diverse m...

Modeling of Human Cytomegalovirus Maternal-Fetal Transmission in a Novel Decidual Organ Culture

“…Indeed, HCMV DNA and gene expression has been found in clinical samples taken from placentas early and late in gestation (45,50,54,68). Accumulating experimental and clinical evidence indicates that, in addition to serving in viral transmission, the placenta may be actively injured by HCMV, conceivably contributing to the observed IUGR and fetal disease (1,50,59,60). The placenta is a chimeric organ, containing both maternal and fetal structures (43) (Fig.…”

Cell-type specific activities of cytomegalovirus GPCR homologues

“…Schleiss et al (2007) found repression of MMP-3 in syncitiotrophoblasts and suggested that HCMV down-regulated genes associated with extracellular matrix formation and stabilization. Yamamoto-Tabata et al (2004) has also found a down-regulation of MMP-2 in HUVECS, uterine microvascular endothelial cells, fibroblasts and cytotrophoblasts and of MMP-9 in cytotrophoblasts and HUVEC upon infection with HCMV.…”

“…HCMV infection has been reported to hinder placental differentiation, to affect tissue integrity and to elicit a proinflammatory response (Benard et al, 2014;Chou et al, 2006;Schleiss et al, 2007).…”

“…Taken together, this could explain the placenta damage and impaired development detected in infections. Moreover, it has also been reported that HCMV infection of trophoblasts can alter signalling pathways, such as Wnt/, expression of adhesion molecules, secretion of cytokines and cellular function, such as migration and invasion (Angelova et al, 2012;Hamilton et al, 2012;Schleiss et al, 2007;van Zuylen et al, 2016;Warner et al, 2012), causing further dysregulation of placenta functions. These changes are linked with higher risks of severe disease in the foetuses and poor pregnancy outcome during the first trimester (Enders et al, 2011;Pass et al, 2006).…”

“…Furthermore, HCMV can hinder trophoblast differentiation, changing the expression of important adhesion proteins, inflammatory molecules and chemotaxis mediators, thus, altering cell functions like invasiveness and placental development (Fisher et al, 2000;Maidji et al, 2007;Pereira & Maidji, 2008;Schleiss et al, 2007).…”