Date of Award

1-1-2016

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biomedical Sciences

Content Description

1 online resource (xvii, 190 pages) : color illustrations

Dissertation/Thesis Chair

Nicholas Mantis

Committee Members

Kimberlee Musser, Joseph Wade, Kathleen McDonough, Karsten Hazlett, Ronald Taylor

Keywords

antibody, cholera, enteric, immunity, mucosal, vaccine, Immunoglobulins, Vibrio cholerae, Epithelial cells

Subject Categories

Immunology of Infectious Disease | Microbiology | Public Health

Abstract

Vibrio cholerae, the causative agent of the severe diarrheal disease cholera, has an estimated worldwide disease burden in the millions and remains a significant public health threat. Immunity to V. cholerae is primarily antibody-mediated and though V. cholerae colonization evokes a mucosal immune response, it is the secretory IgA (SIgA) antibodies produced against bacterial surface antigens, specifically lipopolysaccharide (LPS) that confer protective immunity. SIgA antibodies are thought to function by inhibiting colonization by cross-linking and agglutination of pathogens, thereby limiting access to the epithelium, a process known as immune exclusion. Recent studies in other enteric pathogens have demonstrated that SIgA may function through a range of activities, including inhibiting motility, invasion, and secretion systems required for bacterial pathogenesis. Despite evidence that intestinal immunity to V. cholerae is predominantly mediated by anti-LPS IgA antibodies, the mechanism by which these SIgA antibodies confer protection remains unclear. Thus, the objective of my dissertation was to elucidate the interaction between anti-LPS antibodies and V. cholerae and determine to the impact that antibody binding has on V. cholerae pathogenesis. To characterize the mechanisms of antibody-mediated immunity, I have used monoclonal antibodies (mAbs) that bind epitopes within different regions of the V. cholerae LPS structure and, by comparing the IgA, IgG and Fab fragment derivatives of the mAbs, I was able to assess how antibody-mediated cross-linking and direct antibody binding contribute independently to immunity.

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