title: PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells.
abstract: Congenital infection by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae of the central nervous system, including sensorineural deafness, cerebral palsies or devastating neurodevelopmental abnormalities (0.1% of all births). To gain insight on the impact of HCMV on neuronal development, we used both neural stem cells from human embryonic stem cells (NSC) and brain sections from infected fetuses and investigated the outcomes of infection on Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a transcription factor critical in the developing brain. We observed that HCMV infection dramatically impaired the rate of neuronogenesis and strongly increased PPARγ levels and activity. Consistent with these findings, levels of 9-hydroxyoctadecadienoic acid (9-HODE), a known PPARγ agonist, were significantly increased in infected NSCs. Likewise, exposure of uninfected NSCs to 9-HODE recapitulated the effect of infection on PPARγ activity. It also increased the rate of cells expressing the IE antigen in HCMV-infected NSCs. Further, we demonstrated that (1) pharmacological activation of ectopically expressed PPARγ was sufficient to induce impaired neuronogenesis of uninfected NSCs, (2) treatment of uninfected NSCs with 9-HODE impaired NSC differentiation and (3) treatment of HCMV-infected NSCs with the PPARγ inhibitor T0070907 restored a normal rate of differentiation. The role of PPARγ in the disease phenotype was strongly supported by the immunodetection of nuclear PPARγ in brain germinative zones of congenitally infected fetuses (N = 20), but not in control samples. Altogether, our findings reveal a key role for PPARγ in neurogenesis and in the pathophysiology of HCMV congenital infection. They also pave the way to the identification of PPARγ gene targets in the infected brain.
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.
authors.forename: Maude
authors.initials: M
authors.lastname: Rolland
authors.affiliation: Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Li
authors.affiliation: Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Sellier
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Martin
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.
authors.forename: Teresa
authors.initials: T
authors.lastname: Perez-Berezo
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rauwel
authors.affiliation: I-STEM, INSERM U861, AFM, Evry, France.|CECS, UEVE U861, Evry, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benchoua
authors.affiliation: Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Bettina
authors.initials: B
authors.lastname: Bessières
authors.affiliation: Département d'Anatomie Pathologique, IUCT-Oncopole, Toulouse, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Aziza
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.affiliation: Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Minhua
authors.initials: M
authors.lastname: Luo
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.|Neonatal Unit, Children's Hospital, Toulouse, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Casper
authors.affiliation: I-STEM, INSERM U861, AFM, Evry, France.|CECS, UEVE U861, Evry, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez-Dunia
authors.affiliation: Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Leruez-Ville
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Davrinche
authors.affiliation: Centre de Physiopathologie Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Paul Sabatier, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chavanas
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D002851:Chromatography, High Pressure Liquid; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000151:congenital* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D046529:Microscopy, Electron, Transmission; D058953:Neural Stem Cells / Q000378:metabolism / Q000821:virology*; D055495:Neurogenesis / Q000502:physiology*; D047495:PPAR gamma / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D047495:PPAR gamma