All ETDs from UAB

Advisory Committee Chair

William J Britt

Advisory Committee Members

Linda Wadiche

Hubert Tse

Scott Wilson

Gwendalyn King

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Human cytomegalovirus (HCMV) infection is a major cause of morbidity in infants and children throughout the world. Between 0.2-1.2% of all live births is infected with HCMV in the United States. Approximately 5-15% of these newborn babies will develop long-term neurological damage resulting in motor disorders, mental retardation, and sensorineural hearing loss. Although the neurological sequelae associated with congenital HCMV infections are well characterized, little is known about the pathogenesis of the damage to the central nervous system (CNS). To study the pathogenesis of congenital HCMV infection, we have developed a mouse model in which newborn mice are infected intraperitoneally (i.p.) with a non-lethal dose of murine CMV (MCMV), a virus that has similar genetic background and replication program to HCMV. Following inoculation, the virus infects and replicates in peripheral organs such as liver and spleen. Infected mice then develop viremia that results in the hematogenous spread of the virus to the CNS, including the cochlea and all regions of the brain. Previously, we have described the development of widespread, non-necrotizing but very focal encephalitis in the brain that unexpectedly was associated with global delays in neurodevelopment that were most readily observed in the cerebellar cortex of young mice. These morphogenic alterations included a decreased in cerebellar size and reduction in foliation. Furthermore, altered morphogenesis in the cellular positioning of the cerebellar cortex could be demonstated by the findings of a thinner molecular layer (ML) and internal granule layer (IGL) as well as thicker external granule layer (EGL) where cerebellar granule neuron precursors (CGNPs) actively proliferate during development. Our studies revealed that these abnormalities in cortical development could be attributed to prolonged duration of the cell cycle as well as premature cell cycle exit of CGNP resulting in a delay in migration from EGL to IGL in the cerebellar cortex. In addition, the expression of sonic hedgehog (Shh), a potent mitogen produced by Purkinje neurons, was reduced in MCMV-infected mice cerebella, consistent with the altered CGNP cell cycle progression. Collectively, we demonstrate that compromised CGNP proliferation was a major determinant leading to premature cell cycle exit and differentiation contributing to reduced cerebellar size in MCMV-infected mice. Also utilizing this model, we have previously shown that 50-60% of young adult mice infected as newborns exhibited elevated auditory brainstem response (ABR) thresholds and increased distortion product otoacoustic emissions, indicative of hearing loss in both mice and humans. Histological analyses of the inner ear including the organ of Corti in mice with elevated ABR thresholds revealed uniformly preserved morphology and number of inner and outer hair cells as well as supporting cells. These findings argued for a functional impairment of hair cells in infected mice and not a loss in hair cell number. Interestingly, the number of spiral ganglion neurons (SGN) and synapses connecting cochlear hair cells and SGN nerve terminals were reduced. Furthermore, the stria vascularis exhibited altered morphology in that the expression of proteins associated with tight junctions was decreased in infected mice. As we observed in the brain of infected mice, virus-infected cells were infrequent and widely scattered in the inner ear without a predisposition for one cell type or region. These findings suggested that MCMV infection in newborn mice could lead to structural damage in regions of the inner ear early in the development of auditory pathways and these insults could contribute to impaired auditory function in the mature cochlea of adult mice. The discrepancy between scattered foci of virus-infected cells in the brain and inner ear and global and symmetric neurodevelopmental abnormalities in the CNS suggested that neuroinflammation could represent possible mechanism of pathogenesis of the neurodevelopmental abnormalities associated with congenital HCMV infection. Using this system, we have shown that modulating host inflammatory response to MCMV infection normalized many of the developmental abnormalities in the cerebellar cortex, including the altered in CGNP proliferation. In addition, limiting host inflammatory response also partially corrected the histological abnormalities of SGN loss and improved synaptic transmission and conduction velocity of sound signal. These findings in the cochlea and the cerebellum provide important new insight into the mechanisms of neurological damage that follows HCMV infection during early development and could potentially serve as a foundation for the development of targeted interventions aimed to prevent delayed brain development or hearing loss in infants as a result of in utero HCMV infection.



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