Date

April 2013

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Microbiology and Molecular Immunology

Institution

Oregon Health & Science University

Abstract

Varicella zoster virus (VZV) is a neurotropic alpha-herpesvirus and the causative agent of varicella (chickenpox). Following the establishment of latent infection in the sensory ganglia, age-related decline in T cell immunity or immune suppressive treatments can lead to the reactivation of VZV and the development of herpes zoster (HZ, shingles). HZ is often associated with significant morbidity and occasionally mortality in elderly and immune compromised patients. While current FDA-approved vaccines reduce the number of varicella-related hospitalizations and the burden of HZ disease, both appear to only elicit short-term immunity. Development of more efficacious vaccines and therapeutics requires a better understanding of the host response to VZV. These studies have been hampered by the lack of animal models that fully recapitulate VZV infection in humans. Previous studies from our laboratory have established simian varicella virus (SVV) infection of young rhesus macaques as a robust model with which to study VZV pathogenesis. In this dissertation, we use this model of infection to investigate the contribution of cellular immunity to the resolution of SVV. First, we show evidence of lymphocyte redistribution within the lung following acute SVV infection towards CD8 effector memory (EM) T cells. Our data further indicates that CD4 T cells not only produce essential anti-viral cytokines during acute SVV infection, but also possess cytotoxic capabilities. In addition, we propose a role for plasmacytoid dendritic cells in the initial anti-SVV response in the lung. Using immune cell depleting strategies, we discovered that cellular rather than humoral immunity is essential for the successful resolution of acute SVV infection. More specifically, we show that CD4 T cells are critical for SVV control, and that their function goes well beyond providing help to CD8 T cells and B cells. We also characterized the specificity of the T cell response to SVV during acute and latent infection. Ex vivo analysis of the response to the SVV proteome revealed a group of SVV ORFs that are immunogenic during both acute and latent infection. Lastly, we present preliminary data that suggest a critical role for CD4 T cells in SVV dissemination. The findings presented in this dissertation support previous work indicating the importance of T cell immunity in the resolution of VZV, and lay groundwork for future studies investigating the adaptive immune response to VZV using the robust rhesus macaque model developed in our laboratory.

Identifier

doi:10.6083/M4930R50

School

School of Medicine

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