PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells

PLoS Pathog. 2016 Apr 14;12(4):e1005547. doi: 10.1371/journal.ppat.1005547. eCollection 2016 Apr.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Differentiation / physiology
  • Chromatin Immunoprecipitation
  • Chromatography, High Pressure Liquid
  • Cytomegalovirus Infections / complications*
  • Cytomegalovirus Infections / congenital*
  • Cytomegalovirus Infections / metabolism*
  • Fluorescent Antibody Technique
  • Humans
  • Microscopy, Electron, Transmission
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / virology*
  • Neurogenesis / physiology*
  • PPAR gamma / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tandem Mass Spectrometry

Substances

  • PPAR gamma

Grant support

This study was financially supported by the Institut de la Santé et de la Recherche Médicale (INSERM) (inserm.fr), Centre National de la Recherche Scientifique (CNRS) (cnrs.fr), Université Toulouse Paul Sabatier (UPS) (univ-tlse3.fr), Association Française contre les Myopathies (AFM-Téléthon) (afm-telethon.fr), Assistance Publique-Hôpitaux de Paris (AP-HP) (aphp.fr), Université Paris Descartes (UPD) (parisdescartes.fr) and Chinese Academy of Sciences (CAS) (english.cas.cn). MR was financially supported by UPS. XL was financially supported by CNRS and CAS. YS was financially supported by AP-HP and UPD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.