Date

May 2007

Document Type

Thesis

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

West Nile virus is an arthropod borne virus that can cause severe central nervous system diseases including meningitis and encephalitis. This emerging infectious disease was introduced into North America in 1999 and has since spread throughout the Americas causing thousands of cases of disease. Severe West Nile virus (WNV) disease disproportionately affects the elderly population. This dissertation describes a novel model of WNV infection in aged mice that was developed to study the age-related factors involved in the increased susceptibility of the elderly to WNV. Using this model we have been able to show that aged mice are more susceptible to WNV infection and that deficiencies in the antigen-specific T cell response play a role in this susceptibility. We have characterized the impact of two molecular defects within the antigen-specific T cell compartment that lead to the increased susceptibility of old mice to WNV encephalitis. We have identified defects in production of both Interferon gamma and Granzyme B within WNV-specific T cells. We have also compared and contrasted our model of immune senescence in old mice infected with WNV with the effects of immune senescence on old mice infected with Vaccinia virus. During the development of this model we were able to identify WNV-encoded MHC class I and class II-restricted CD8 and CD4 T cell epitopes and characterize the functional epitope-specific T cell response that is elicited in WNV infected C57BL/6 mice (H-2b haplotype). These newly described epitopes are currently being used to characterize the development and maintenance of memory T cells in old and adult mice as well as evaluate novel vaccine vectors and treatments designed to reverse the susceptibility of old mice to serious West Nile virus infection.

Identifier

doi:10.6083/M4RN35T5

School

School of Medicine

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