[en] 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 (PPARgamma), a transcription factor critical in the developing brain. We observed that HCMV infection dramatically impaired the rate of neuronogenesis and strongly increased PPARgamma levels and activity. Consistent with these findings, levels of 9-hydroxyoctadecadienoic acid (9-HODE), a known PPARgamma agonist, were significantly increased in infected NSCs. Likewise, exposure of uninfected NSCs to 9-HODE recapitulated the effect of infection on PPARgamma 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 PPARgamma 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 PPARgamma inhibitor T0070907 restored a normal rate of differentiation. The role of PPARgamma in the disease phenotype was strongly supported by the immunodetection of nuclear PPARgamma in brain germinative zones of congenitally infected fetuses (N = 20), but not in control samples. Altogether, our findings reveal a key role for PPARgamma in neurogenesis and in the pathophysiology of HCMV congenital infection. They also pave the way to the identification of PPARgamma gene targets in the infected brain.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Rolland, Maude ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo of Molecular Immunol. and Signal Transduction
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