Cytomegalovirus infection triggers the secretion of the PPARγ agonists 15-hydroxyeicosatetraenoic acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in human cytotrophoblasts and placental cultures

Abstract

Introduction: Congenital infection by human cytomegalovirus (HCMV) is a leading cause of congenital abnormalities of the central nervous system. Placenta infection by HCMV allows for viral spread to fetus and may result in intrauterine growth restriction, preeclampsia-like symptoms, or miscarriages. We previously reported that HCMV activates peroxisome proliferator-activated receptor gamma (PPARγ) for its own replication in cytotrophoblasts. Here, we investigated the molecular bases of PPARy activation in infected cytotrophoblasts. Results: We show that onboarded cPLA2 carried by HCMV particles is required for effective PPARy activation in infected HIPEC cytotrophoblasts, and for the resulting inhibition of cell migration. Natural PPARy agonists are generated by PLA2 driven oxidization of linoleic and arachidonic acids. Therefore, using HPLC coupled with mass spectrometry, we disclosed that cellular and secreted levels of 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE) were significantly increased in and from HIPEC cytotrophoblasts at soon as 6 hours postinfection. 13-HODE treatment of uninfected HIPEC recapitulated the effect of infection (PPARγ activation, migration impairment). We found that infection of histocultures of normal, first-term, human placental explants resulted in significantly increased levels of secreted 15-HETE and 13-HODE. Conclusion: Our findings reveal that 15-HETE and 13-HODE could be new pathogenic effectors of HCMV congenital infection They provide a new insight about the pathogenesis of congenital infection by HCMV.