Advisory Committee Chair
William Britt
Advisory Committee Members
Scott Barnum
Michael Brenner
Lynn Dobrunz
Scott M Wilson
Document Type
Dissertation
Date of Award
2007
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Congenital Human Cytomegalovirus (HCMV) infection represents a significant cause of morbidity and mortality in infants and children. While most of the systemic damage incurred by the infant in the course of the infection resolves without permanent consequence, the pathological manifestations of infection in the central nervous system (CNS) are often permanent. Children born with congenital HCMV infection may exhibit hearing loss and cognitive impairment in various degrees. These neurological disabilities are correlated with pathological findings in various permutations including infection of the inner ear, ventricular calcifications, ventriculomegaly, microgyria, lissencephaly, and cerebellar hypoplasia. To develop a therapeutic or preventive strategy, HCMV infection must be studied experimentally in animal model systems. The murine model is suitable to study the effects of Cytomegalovirus (CMV) infection on brain development. In the murine model described herein, intra-peritoneal inoculation of newborn mice with MCMV leads to a systemic viral infection and spread to the CNS by 5 days postinoculation (dpi). The CNS infection largely resolves by 14 dpi. The cerebellum is the brain region most actively developing during 5-14 days post-natal in the mouse coincident with MCMV infection. We observed focal cerebellar developmental abnormality superimposed upon widespread and symmetrical developmental changes, associated with widely scattered foci of virus infection. This discrepancy between the spatial distribution of viral infection and the widespread developmental abnormality led iii to the hypothesis that soluble immune response molecules were responsible for the developmental perturbation. The proposed mechanism of immune mediated developmental neuropathology constitutes a break with the existing literature on animal models of HCMV infection in the CNS because previous work in animal models has focused on the direct effects of virus infection on cells rather than indirect effects such as CNS inflammatory response. This inflammatory response was correlated temporally and spatially with histological, functional, and molecular abnormalities in cerebellar development.
Recommended Citation
Koontz, Thadeus B., "MCMV Induced Cerebellar Maldevelopment" (2007). All ETDs from UAB. 3736.
https://digitalcommons.library.uab.edu/etd-collection/3736