Date of Award

12-26-2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

David S. Bradley

Abstract

Yersinia pestis, the causative agent of plague, is endemic to most of the world. Y. pestis' potential threat as a biological warfare agent has drawn increased attention to pathogenesis and vaccine research for the plague. A number of characteristics related both to the host response to, and bacterial pathogenesis of, Y. pestis were examined. To investigate the potential role of MHC Class II antigen presentation during the plague, HLA-DQ8αβ transgenic mice were infected with Y. pestis. DQ8 mice demonstrated a greatly enhanced age-dependent resistance to Y. pestis infection with females more resistant than males, mimicking gender differences in human plague, and a strong IgG response, compared to very susceptible outhred Swiss Webster mice that displayed neither a gender difference nor an elevated IgG response. In addition, mast cells were also demonstrated to be involved in the DQ8 strain-associated resistance to Y. pestis infection. The Y. pestis vaccine that has shown the most potential consists of two Y. pestis proteins, Fraction 1 (F 1) and LcrV. However, immunological pitfalls have been identified for the F1/V vaccine and the discovery of other protective antigens is highly desirable. We screened seventeen Y. pestis candidates. Identifying potential proteins that are both antigenic and protective against Y. pestis proved to be difficult. Only YscF, the needle structure of the type three secretion system, conferred partial protection against F1+ and F1-Y. pestis strains. The contribution of the F1 capsule to virulence of Y. pestis is unclear. Previous studies report conflicting results for various F1- strains. It is of note, that none of these studies directly mutated the caf1 gene, but rather prevented F1 expression by mutagenesis of various chaperones and usher proteins. We demonstrated that deletion of the caf1 gene resulted in significant attenuation of the plague in several different mouse strains. Y. pestis' Pla protease aids in the dissemination of Y. pestis throughout the body. However, it is unclear if Pla is necessary for virulence. We demonstrated that systemic infection with Pla- Y. pestis was severely attenuation. These findings provide new insight into both protective responses to, and the virulence factors of, Y. pestis.

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