title: 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: BACKGROUND
  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 PPARγ activation in infected cytotrophoblasts.
  
  
  RESULTS
  We show that onboarded cPLA2 carried by HCMV particles is required for effective PPARγ activation in infected HIPEC cytotrophoblasts, and for the resulting inhibition of cell migration. Natural PPARγ 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 post infection. 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Kaoutar
authors.initials: K
authors.lastname: Leghmar
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Maude
authors.initials: M
authors.lastname: Rolland
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Martin
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rauwel
authors.affiliation: MetaToul Lipidomics facility, Toulouse, France; I2MC INSERM U1048, Toulouse, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.affiliation: MetaToul Lipidomics facility, Toulouse, France; I2MC INSERM U1048, Toulouse, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Le Faouder
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; Neonatal Unit, Children's Hospital, Toulouse, France.
authors.forename: Mélinda
authors.initials: M
authors.lastname: Bénard
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; Neonatal Unit, Children's Hospital, Toulouse, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Casper
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Davrinche
authors.affiliation: INSERM UMR-S1139, Paris, France; Université Paris Descartes, Paris, France; PremUP, Fondation, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fournier
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chavanas
mesh_terms: D002465:Cell Movement; D003587:Cytomegalovirus / Q000502:physiology*; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D008041:Linoleic Acids / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D011247:Pregnancy; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism* / Q000821:virology*
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D008041:Linoleic Acids; D047495:PPAR gamma; C024348:13-hydroxy-9,11-octadecadienoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D054510:Phospholipases A2, Cytosolic