Congenital cytomegalovirus (“CMV”) infection is a leading prenatal cause of intellectual disability, nonhereditary sensorineural hearing loss, and can bring about other long-term neurodevelopmental disabilities including cerebral palsy, vision impairment, and seizures.
Approximately 10% of neonates with congenital CMV infection show symptoms of disease at birth. 10% to 15% of congenitally infected newborns that are asymptomatic at birth show neurological disorder later in infancy. Infants most at risk of suffering from neurodevelopmental sequelae are those infected as a result of primary maternal CMV infection.
Ultrasound image of an unborn child
Studies have shown that CMV preferentially infects stem cells in the brain and prevents them from differentiating into neurons, the brain’s signaling cells. This impairment reduces the total number of neurons and may lead to the neurological sequelae seen in some congenital CMV infections. However, the specific cellular and molecular mechanisms underlying the impaired neuron generation following CMV infection have remained elusive.
To gain insight into the underlying causes of CMV disease development, researchers from Universite de Toulouse in France used neural stem cells (“NSCs”) from human embryonic stem cells to determine the pathogenesis of CMV in vitro. In a second related study, the team examined brain sections from CMV infected fetuses.
The researchers were able to confirm that CMV infection impairs neuron generation in vitro, and then began to focus their study on a ligand that showed increased expression in infected cultures, Peroxisome Proliferator-Activated Receptor Gamma (“PPARγ”). PPARγ plays a key role in regulating cellular function and tissue homeostasis. Previous studies have shown that the protein is critical to the activation, proliferation, and differentiation of embryonic NSCs. Given its role in brain development, the researchers reasoned that CMV infection may be increasing PPARγ and leading to the neurodevelopmental issues.
The French study found that CMV increased PPARγ activity and concentration levels in infected stem cells compared to uninfected stem cells. In these models, increased PPARγ activity appears to be stimulated by a known activator of PPARγ, called 9-HODE, which also significantly increased in NSCs following infection. Researchers hypothesize that CMV may catalyze the generation of 9-HODE, which, in turn, increases PPARγ levels.
Increased PPARγ activity was shown to impair neuronal differentiation of NSCs, even without infection, demonstrating that activation of this pathway could be a leading cause of impaired neuron generation. This link was further evidenced when the researchers treated CMV-infected stem cells with a drug that inhibits PPARγ and found that the cells resumed the normal rate of neural cell production after treatment.
To strengthen the relevance of these in vitro findings to human disease, the team investigated PPARγ expression in brain samples from infected fetuses that had not been carried to term. By comparing the infected brain samples to uninfected controls, the researchers found that PPARγ was present in the central nucleus of cells in brain regions where healthy, active neuron production normally occurs. This phenomenon was not observed in healthy tissue samples.
In the U.S., each year approximately 5,000 U.S. infants will develop permanent problems due to CMV, some of them severe, including deafness, blindness, and mental retardation. The direct annual costs of caring for these patients are estimated at $1 to $2 billion. This study reveals the potentially important role PPARγ may play in neuron development and in the pathophysiology of congenital CMV infection. While early, the research could one day lead to the development of new prognostic or therapeutic tools.