Activation of Peroxisome Proliferator-Activated Receptor Gamma by Human Cytomegalovirus for De Novo Replication Impairs Migration and Invasiveness of Cytotrophoblasts from Early Placentas

Abstract

Human cytomegalovirus (HCMV) contributes to pathogenic processes in immunosuppressed individuals, in fetuses, and in neonates. In the present report, by using reporter gene activation assays and confocal microscopy in the presence of a specific antagonist, we show for the first time that HCMV infection induces peroxisome proliferator-activated receptor gamma (PPAR␥) transcriptional activity in infected cells. We demonstrate that the PPAR␥ antagonist dramatically impairs virus production and that the major immediateearly promoter contains PPAR response elements able to bind PPAR␥, as assessed by electrophoretic mobility shift and chromatin immunoprecipitation assays. Due to the key role of PPAR␥ in placentation and its specific trophoblast expression within the human placenta, we then provided evidence that by activating PPAR␥ human cytomegalovirus dramatically impaired early human trophoblast migration and invasiveness, as assessed by using well-established in vitro models of invasive trophoblast, i.e., primary cultures of extravillous cytotrophoblasts (EVCT) isolated from first-trimester placentas and the EVCT-derived cell line HIPEC. Our data provide new clues to explain how early infection during pregnancy could impair implantation and placentation and therefore embryonic development.

Evidence Implicating Peroxisome Proliferator-Activated Receptor-γ in the Pathogenesis of Preeclampsia

“…The use of rosiglitazone in these studies has been shown to inhibit the trophoblastic invasion process 28 and, in particular, to inhibit extravillous cytotrophoblasts invasion and impair early human trophoblast migration. 29 In contrast, PPAR-␥ antagonists were shown to promote extravillous cytotrophoblast cell invasion. 30 However, results from other studies are more consistent with our findings.…”

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

“…40 Activation of PPAR-␥ by human cytomegalovirus also impaired early human trophoblast migration and invasiveness in the EVCT. 41 In recent studies, both Nadra et al 42 and Schaiff et al 43 demonstrated adverse placental development after rosiglitazone administration to healthy pregnant mice, including disorganization of placental layers, altered placental microvasculature, decreased placental expression of angiogenic factors, and thinning of the spongiotrophoblast layer and dilated labyrinthine blood spaces. In both studies, rosiglitazone was administrated during the early stages of gestation and at considerably higher concentrations (30 to 100 mg/kg per day) then that used in the present study (5 mg/kg per day).…”

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

“…In addition, the screen does not rule out a role for nuclear receptors that do not meet the cut off. However, PPARγ, which is already known for its positive role during HCMV infection (17), was classified as a hit in the screen, suggesting our methodology was robust and may identify other host factors that play a role during viral replication.…”

“…Cortisol, the glucocorticoid receptor ligand, enhanced virus production in human embryonic kidney cells (16). Most recently, a PPAR response element was described within the MIEP, and a PPARγ antagonist reduced viral protein expression, lipid droplet formation, and virus production (17).…”