Production of Proinflammatory Cytokines by Syncytiotrophoblasts Infected with Human Cytomegalovirus Isolates

Ij, Kovács; Hegedűs, Kinga; A, Pal; Pusztai, Rozália

doi:10.1016/j.placenta.2006.09.008

Cited by 16 publications

(11 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, these observations support our findings of ssRNA modulation of IL-6 and IL-8 in first trimester trophoblast cells. Moreover, studies using CMV have shown that viral infection of first trimester trophoblast cells also upregulate IL-6 and IL-8 46,47. Our observation that viral ssRNA also induces a strong IFN® response in the trophoblast is in keeping with the ability of the placenta to generate a specific anti-viral response.…”

Section: Discussionsupporting

confidence: 77%

Viral ssRNA Induces First Trimester Trophoblast Apoptosis through an Inflammatory Mechanism

Aldo

Mulla

Romero

et al. 2010

American J Rep Immunol

View full text Add to dashboard Cite

Problem-Infection during pregnancy represents a significant cause of mobility and mortality. While viruses pose a major threat, little is known about their effect on early pregnancy, or the mechanisms involved. The objective of this study was to characterize the trophoblast response following exposure to viral ssRNA.Method of study-First trimester trophoblast cells were treated with or without viral ssRNA. Cytokine production was measured by multiplex analysis and ELISA. Apoptosis was determined using Hoescht staining, cell viability, and caspase activity assays.Results-Treatment of trophoblasts with viral ssRNA increased their secretion of IL-8, IL-6 and IFNβ. However, the ssRNA also induced trophoblast apoptosis. To test whether the viral ssRNAinduced inflammatory response was responsible for this induction of apoptosis, conditioned media (CM) from trophoblasts was added to a fresh culture of cells. The CM from viral ssRNA-treated induced higher levels of trophoblast apoptosis than the control CM. Moreover, recombinant IFNβ induced trophoblast apoptosis.Conclusion-We demonstrate that viral ssRNA induces a pro-inflammatory and type I interferon response in the trophoblast, and that this inflammatory process may indirectly induce trophoblast apoptosis. These results provide a novel mechanism by which certain viral infections might compromise placental integrity and function, and therefore, pregnancy outcome.

show abstract

Section: Discussionsupporting

confidence: 77%

Viral ssRNA Induces First Trimester Trophoblast Apoptosis through an Inflammatory Mechanism

Aldo

Mulla

Romero

et al. 2010

American J Rep Immunol

View full text Add to dashboard Cite

show abstract

“…Dysregulation of proinflammatory and angiogenic cytokines plays a major role in HCMV placental pathology [26, 27]. We examined 24 h supernatants from SBCMV-infected primary human placental pericytes along with mock-infected cells and cells exposed to heat-killed virus for changes in secretion profiles using Luminex assays (Fig.…”

Section: Resultsmentioning

confidence: 99%

Placental pericytes and cytomegalovirus infectivity: Implications for HCMV placental pathology and congenital disease

Aronoff

Correa

Rogers

et al. 2017

American J Rep Immunol

View full text Add to dashboard Cite

Problem Placental pericytes are essential for placental microvascular function, stability, and integrity. Mechanisms of HCMV pathogenesis incorporating placental pericytes are unknown. Method of Study HCMV infected placental tissue was stained by dual-labeled immunohistochemistry. Primary placental pericytes, cytotrophoblasts, and villous fibroblasts were exposed to HCMV; infectivity was analyzed by microscopy and immunofluorescence. Cytokine expression was examined by Luminex assay. A HCMV-GFP recombinant virus was used to examine replication kinetics. Results Immunohistochemistry showed HCMV in trophoblast and the villous core with T-cell and macrophage infiltration. SBCMV-infected pericytes showed dysregulation of proinflammatory and angiogenic cytokines when compared to control cells. A tri-cell model of the villous floor showed a unique expression profile. Finally, we show pericytes infected in vivo with HCMV in placental tissue from a congenitally infected child. Conclusions Placental pericytes support HCMV replication, inducing proinflammatory and angiogenic cytokines that likely contribute to viral dissemination, placenta inflammation, and dysregulation of placental angiogenesis.

show abstract

“…We and others have reported that CMV infection mediates alterations in cytokines, cell-cell and cell-matrix adhesion molecules, key integrins, and peroxisome proliferator-activated receptor ␥ (PPAR␥) signaling in trophoblasts (8,15,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In vitro, CMV dramatically reduces invasion and migration of trophoblasts (25,32).…”

mentioning

confidence: 99%

Human Cytomegalovirus Modulates Expression of Noncanonical Wnt Receptor ROR2 To Alter Trophoblast Migration

Zuylen

Ford

Wong

et al. 2016

J Virol

View full text Add to dashboard Cite

Maternal primary cytomegalovirus (CMV) infection, reactivation, or reinfection with a different viral strain may cause fetal injury and adverse pregnancy outcomes. Increasing evidence indicates that fetal injury results not only from direct viral cytopathic damage to the CMV-infected fetus but also from indirect effects through placental infection and dysfunction. CMV alters Wingless (Wnt) signaling, an essential cellular pathway involved in placentation, as evidenced by reduced transcription of canonical Wnt target genes and decreased Wnt3a-induced trophoblast migration. Whether CMV affects the noncanonical Wnt signaling pathway has been unclear. This study demonstrates for the first time that CMV infection inhibits Wnt5a-stimulated migration of human SGHPL-4 trophoblasts and that inhibition of the pathway restores normal migration of CMV-infected cells. Western blot and real-time PCR analyses show increased expression of noncanonical Wnt receptor ROR2 in CMV-infected trophoblasts. Mimicking the CMV-induced ROR2 protein expression via ectopic expression inhibited Wnt5a-induced trophoblast migration and reduced T cell-specific factor (TCF)/lymphoid enhancer-binding factor (LEF)-mediated transcription as measured using luciferase reporter assays. Gene silencing using small interfering RNA (siRNA) duplexes decreased ROR2 transcript and protein levels. In contrast, proliferation of SGHPL-4 trophoblasts, measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was not affected. The siRNA-mediated downregulation of ROR2 in trophoblasts rescued CMV-induced reduction in trophoblast migration. These data suggest a mechanism where CMV alters the expression of the Wnt receptor ROR2 to alter Wnt5a-mediated signaling and inhibit trophoblast motility. Inhibition of this mechanism may be a target for therapeutic intervention for CMV-induced placental damage and consequent fetal damage in congenital CMV infections. IMPORTANCEMaternal primary cytomegalovirus (CMV) infection, reactivation, or reinfection with a different viral strain may cause fetal injury and adverse pregnancy outcomes. Increasing evidence indicates that fetal injury results not only from direct viral cytopathic damage to the CMV-infected fetus but also from indirect effects through placental infection and placental dysfunction. No effective therapy is currently proven to prevent or treat congenital CMV infection. Understanding the molecular underpinnings of CMV infection of the placenta is essential for therapeutic innovations and vaccine design. CMV alters canonical Wingless (Wnt) signaling, an essential cellular pathway involved in placental development. This study suggests a mechanism in which CMV alters the expression of noncanonical Wnt receptor ROR2 to alter motility of placental cells, which has important implications in the pathogenesis of CMV-induced placental dysfunction. Inhibition of this mechanism may be a target for therapeutic intervention for CMV-induced placental damage and consequent fetal damage in con...

show abstract

Production of Proinflammatory Cytokines by Syncytiotrophoblasts Infected with Human Cytomegalovirus Isolates

Cited by 16 publications

References 24 publications

Viral ssRNA Induces First Trimester Trophoblast Apoptosis through an Inflammatory Mechanism

Viral ssRNA Induces First Trimester Trophoblast Apoptosis through an Inflammatory Mechanism

Placental pericytes and cytomegalovirus infectivity: Implications for HCMV placental pathology and congenital disease

Human Cytomegalovirus Modulates Expression of Noncanonical Wnt Receptor ROR2 To Alter Trophoblast Migration

Contact Info

Product

Resources

About