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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.
Highlights
Congenital infection by human cytomegalovirus (HCMV) is a leading cause of permanent abnormalities of the central nervous system [1]
We found increased peroxisome proliferator-activated receptor γ (PPARγ) expression in brains of in utero infected fetuses, but not in controls, suggesting that PPARγ is a key effector of HCMV infection in vivo
Our study provides new insights on the pathogenesis of HCMV infection and paves the way to the discovery of PPARγ-related molecules secreted in the infected brain
Summary
Congenital infection by human cytomegalovirus (HCMV) is a leading cause of permanent abnormalities of the central nervous system [1]. About 1% of newborns are congenitally infected with HCMV each year in the USA, as a result of either primary infection of a seronegative mother, or reinfection / viral reactivation in a seropositive mother during pregnancy. Ten percent of congenitally infected newborns are symptomatic at birth, and most of them (60– 90%) display neurological sequelae [2]. 10 to 15% of congenitally infected newborns that are asymptomatic at birth show neurological disorder with onset later in infancy [2]. Patients with permanent sequelae represent up to 0.1–0.2% of all live births (>5500 per year in the USA). Considering the dramatic health and societal burden of congenital HCMV infection, it is clear that a better insight on its pathogenesis is urgently needed to provide new therapeutic and prognostic tools
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