Neuropathogenesis of congenital cytomegalovirus infection: Disease mechanisms and prospects for intervention

Congential CMV infection is the predominant cause of developmental neurological disabilities in the United States. It most frequently begins as a primary infection in the pregnant mother, who may be exposed to several risk factors, including her own CMV-infected children who shed infectious virus. Prior exposure to CMV markedly reduces the possibility of fetal infection but does not preclude the virus from crossing the placenta to infect the fetus. Not only does the infected placenta serve as an amplifying reservoir, but CMV infection may also cause placental insufficiency that result in fetal pathologies. Gestational age at infection greatly influences neurological outcomes in the fetus. However, the combination of factors that render the developing brain susceptible to CMV infection is poorly understood. CMV infection of the fetus may alter the "normal blueprint" of the developing brain, thus resulting in long-term neurological sequelae. Studies that investigate mechanisms that alter developmental paradigms will help elucidate CMV neuropathogenesis and explain the clinical outcomes of congenital CMV infection. Neural stem cells in the fetal brain appear to be the predominant cell type affected during development by CMV. There is an abundance of neural stem cells in the fetal brain, and their increased susceptibility to viral infection explains the predominance of nerurological sequelae associated with congenital CMV infection. Some possible mechanisms of developmental disruption due to CMV infection include (i) the loss of neural stem cells or intermediate progenitors, the building blocks of the developing brain, due to infection, which may have potential effects on brain size and maturation (165); (ii) alterations in stem cell migration and fate of cell differentiation, processes which are critical for normal pattering and function of neural structures; (iii) infection of astroglia, which may disrupt their normal supportive functions in the brain that are a critical for neural circuitry guidance, synaptic integration, and development of the functionally intergrated mature neuron (160); and (iv) alterations in the microenvironment of the developing brain due to cytokines and soluble factors generated by resident glial cells (microglia and astrocytes) and infiltrating immune cells, which may result in neurotoxicity (68) and altered neuronal physiology (116) and induce abnormal developmental cues in the fetal brain (Fig. 4). All these mechanisms may potentially affect the developmental patterning of the brain. Antiviral drugs are available for treatment of congenital CMV infection, and there is evidence that therapy ameliorates the severity of one of the CNS complications of infection, SNHL. Long-term neurodevelopmental follow-up studies should further clarify the value of antiviral therapy in congenitally infected infants. Uncontrolled studies of therapy in utero with CMV immune globulin have suggested an impact on neuropathogenesis, and controlled trials should be conducted with pregnant women. Finally, CMV vaccines may hold the greatest promise in reducing the neurodevelopmental consequences of congenital infection, although the immune correlates of protection of the fetus remain incompletely defined. Preclinical study with relevant animal models may provide insights into strategies that bear further testing in human clinical trials. Until more-effective interventions are available, better education of women of child-bearing age will be important. Only with increased public awareness of the urgency of this problem can the societal and political forces necessary to effect changes be marshaled. These changes include increased funding for the study of the pathogenesis of congenital CMV and an increased sense of urgency in conducting clinical vaccine trials. Web-based information from both the Centers for Disease Control (http://www.cdc.gov/cmv/) and parent support groups founded by individuals who have children afflicted with congenital CMV (http://www.cmvfoundation.org) can be an effective conduit of knowledge and perspective that help to increase pubic awareness of this urgent problem.