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

作者：Maude Rolland, Xiaojun Li, Yann Sellier, Hélène Martin, Teresa Pérez, Benjamin Rauwel, Alexandra Benchoua, Bettina Bessières, Jacqueline Aziza, Nicolas Cénac, Min‐Hua Luo, Charlotte Casper, Marc Peschanski, Daniel Gonzalez‐Dunia, Marianne Leruez‐Ville, Christian Davrinche, Stéphane Chavanas · 发表于：PLoS Pathogens · 年份：2016 · DOI：10.1371/journal.ppat.1005547 · 被引用次数：48 · 研究领域：Cytomegalovirus and herpesvirus research、Metabolism and Genetic Disorders、RNA regulation and disease

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 nuc...