New Insights about Congenital Infection by Human Cytomegalovirus: Unveiling the Role of PPARγ

Abstract

Congenital infection by human cytomegalovirus (HCMV) might result in permanent neurological sequelae, including sensorineural deafness, cerebral palsies or devastating neurodevelopmental abnormalities. Neural progenitors have been suspected to be key targets of infection, hence a number of studies have shown that HCMV is able to infect neural cells and alter their differentiation. However, little was known about the molecular and genetic bases underlying homeostatic changes in the infected progenitor. We recently disclosed that Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a transcription factor of the nuclear receptor superfamily, is a key determinant of HCMV pathogenesis in the developing brain. Using neural stem cells from human embryonic stem cells, we showed that HCMV infection strongly increases levels and activity of PPARγ in NSCs. Further in vitro experiments showed that PPARγ activity inhibits the neuronogenic differentiation of NSCs into neurons. Consistently, increased PPARγ expression was found in brain section of fetuses infected by HCMV, but not in uninfected controls, what strongly supported the in vitro data. Here we review and discuss past and recent findings on the neuropathogenesis of HCMV congenital infection.