All ETDs from UAB

Advisory Committee Chair

William J Britt

Advisory Committee Members

Peter D Burrows

Kent T Keyser

Etty Benveniste

Lucas Pozzo-Miller

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Congenital human cytomegalovirus (HCMV) infection is a complex cause of central nervous system (CNS) disease. Infection with HCMV during pregnancy results in virus transmission across the placenta and infection of the fetus. With a seroconversion rate in pregnant women between 1% and 4%, HCMV is the most frequently transmitted virus from mother to developing child. Each year between 2,000 and 4,000 infants will suffer from long-term neurologic deficits as a result of congenital infection. The well documented CNS sequelae resulting from congenital HCMV infection have described a wide range of damage without a specific set of pathologic markers for disease. Together these findings have left the mechanism(s) underlying aberrant CNS development and neurologic disease in congenitally infected infants difficult to pinpoint. Congenital HCMV infection results in focal areas of encephalitis and gliosis in the developing brain; however CNS pathology appears symmetric and diffuse. These findings suggest that cytopathology resulting from direct viral infection is limited and likely cannot account for the global CNS damage reported following in utero HCMV infection. In order to study the mechanism(s) of CMV infection underlying abnormal CNS development, we developed a mouse model characterized by perhiperhal infection of newborn mice with non-lethal doses of murine cytomegalovirus (MCMV). In our model, viral replication and spread are similar to that reported following human CMV infection. Additionally, MCMV infection of neonatal mice recapitulates several aspects of the CNS pathology documented following congenital HCMV infection. MCMV infection of newborn mice results in a large induction of inflammatory responses within the CNS coinciding with the appearance of CNS pathology. For this reason, we hypothesized that soluble mediators of inflammation alter the normal development of the brain. Utilizing this model, we have shown that modulating host inflammatory responses to MCMV infection corrects developmental abnormalities in the neonatal mouse brain. In addition, our work has revealed a potentially damaging infiltrating monocyte population within the CNS of MCMV infected neonates. Further studies utilizing this mouse model may elucidate specific mechanisms of CNS disease subsequent to CMV infection during development, leading to new therapeutic interventions for the treatment of infants congenitally infected with HCMV.

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