All ETDs from UAB

Advisory Committee Chair

William J Britt

Advisory Committee Members

Scott Barnum

Peter Burrows

Vithal Ghanta

Allan Zajac

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cytomegalovirus (CMV) is the most frequent cause of congenital brain abnormalities and can lead to lifelong neurological sequalae. Although the brain is a major target in congenital CMV infection, little is known about the long-term effects of infection of the central nervous system (CNS) following acute infection and the resulting neuroimmune responses involved. Due to species-specificity of HCMV, we use a mouse model to study the pathogenesis of HCMV infection of the developing CNS. Newborn mice peripherally infected with murine CMV (MCMV) develop high levels of viremia and subsequent productive infection in the brain parenchyma. CD8+ T lymphocytes are essential for the control of productive MCMV infection in the CNS and are retained in the tissue long after acute infection. To define the role and maintenance of brain CD8+ memory T cells during chronic MCMV infection, we examined CD8+ T cells in the brain as late as two years post infection (p.i.). In the later phases of infection following newborn peripheral MCMV infection, CD8+ memory cells in the brain displayed markers of tissue resident memory cells (TRM). Although they appeared to persist long-term, they lacked the same survival factors as memory T cells within secondary lymphoid organs. In mice persistently infected with MCMV from birth, brain CD8+ memory T cells showed poor proliferative activity, but remained functional by ex vivo and in vivo analyses suggesting an active role in immunosurveillance within the CNS. The retention of memory CD8+ T cells in the brain was associated with viral persistence in the CNS as well as prolonged inflammation. A sustained inflammatory environment in the CNS along with viral persistence may play a role in the functional reprogramming of CD8+ memory cells to remain long-lived without undergoing terminal differentiation. Additionally, to understand the mechanisms of immune cell trafficking to the MCMV-infected CNS, we identified a substantial fraction of mononuclear cells in the CNS to express CCR5, the receptor for the chemokine CCL5 (C-C motif ligand 5), also known as RANTES (regulated on activation normal T cell expressed and secreted). To determine if CCR5 is critical for CD8+ T cell infiltration into the MCMV infected neonatal brain, CCR5-/- mice were infected with MCMV. Infection was uniformly lethal to CCR5-/- mice by PN day 13. Although there was an overall decrease in leukocyte infiltration to the CNS in CCR5-/- mice, we observed an increase in CD8+ T cell frequency and magnitude in the CNS in CCR5-/- mice. The phenotype of recruited CD8+ T cells exhibited partial activation and displayed deficits in IFN-γ and TNF-α production following peptide stimulation. Collectively our results suggest that following MCMV infection, virus-specific CD8+ T cells represent a unique population of memory cells that control persistent viral infection in the CNS and particularly require CCR5 which promoted the maturation and optimal generation of effector antiviral responses in the brain.

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