Advisory Committee Chair
William J Britt
Advisory Committee Members
Scott Barnum
Suresh Boppana
Lou Justement
Harald Sontheimer
Document Type
Dissertation
Date of Award
2007
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Congenital HCMV infection of the developing brain is the leading viral cause of mental retardation and sensorineural hearing loss. To elucidate the pathogenesis of congenital HCMV CNS infections, we developed a small animal model of CMV infection where newborn Balb/c mice are peripherally inoculated with murine cytomegalovirus. In this model we observed transient deficits in cerebellar/hindbrain development as well as the recruitment of peripheral immune effector cells to the CNS parenchyma. CD8+ T-lymphocytes were the predominant mononuclear cellular infiltrates in the brain and immune-depletion of CD8+ cells resulted in increased viral genome copy numbers in the CNS. CD8+ T-lymphocytes exhibited an activated phenotype and were primarily specific against the IE1-168 epitope of MCMV. Ex-vivo stimulation of brain T-lymphocytes with IE1-168 peptide resulted in increased IFN-γ and TNF-α production as well as degranulation as shown by increased surface staining with CD107a. Adoptively transferred brain mononuclear cells from neonatally infected animals were able to control MCMV replication in immune incompetent, MCMV infected adult mice. A substantial fraction of CD8+ T-lymphocytes in the CNS expressed CCR5 early in infection. To determine if CCR5 is critical for mononuclear cell infiltration into the MCMV infected neonatal brain, CCR5-/- mice were infected with MCMV. Infection was completely lethal to CCR5-/- mice by PN day 13. There was an overall decrease in leukocyte infiltration to the CNS in CCR5-/- animals. However, there ii was an unexpected increase in CD8+ T-lymphocyte frequency and magnitude in the CNS of MCMV infected CCR5-/- mice. These CD8+ T-lymphocytes primarily displayed a partially activated phenotype and displayed deficits in IFN-γ and TNF-α production following peptide stimulation. Loss of CCR5 did not yield differences in CNS viral genome copy number between wild type and CCR5-/- animals. Together, these results suggest a role for CD8+ T-lymphocytes in the control of MCMV growth in the newborn CNS. Additionally, our results suggest that CCR5 does not play a role in T-lymphocyte recruitment but it could potentially promote CD8+ T-lymphocyte maturation in MCMV infected animals.
Recommended Citation
Bantug, Glenn Robert Burgner, "Cd8+ T-Lymphocytes And The Control Of Cytomegalovirus Infection Of The Newborn Central Nervous System" (2007). All ETDs from UAB. 3662.
https://digitalcommons.library.uab.edu/etd-collection/3662