Advisory Committee Chair
John F Kearney
Advisory Committee Members
David D Chaplin
Charles O Elson
Robinna G Lorenz
Charles L Turnbough Jr
Document Type
Dissertation
Date of Award
2009
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
cillus anthracis is a gram-positive, spore forming bacterium that causes infection through three routes: cutaneous, gastrointestinal and pulmonary. Historically, anthrax pathogenesis was thought to be initiated via the uptake of spores by resident macrophages, which then transited to the regional lymph nodes. While en-route, the spores germinated and developed into bacilli within the phagolysosome, escaped into the cytoplasm, killed the cell and eventually the host. Following the recent use of B. anthracis as a biological weapon, researchers began to reevaluate anthrax pathogenesis in order to develop novel treatments. One aspect of anthrax pathogenesis that saw renewed interest was the intracellular fate of B. anthracis spores. It was previously assumed that the durability of the endospore facilitated the survival of B. anthracis within the phagolysosome. However, mounting evidence suggests that the intracellular outgrowth of B. anthracis within professional phagocytic cells is actually a low probability event. Cationic peptides were among the first lysosomal components identified that were capable of killing germinating spores as well as the vegetative form of B. anthracis. The goal of this dissertation was to determine whether cationic peptides contribute to host defense against anthrax infection, as well as the therapeutic potential of cationic peptide administration following spore challenge. We chose to focus on a family iii of mammalian cationic peptides known as cathelicidins, which are stored at high concentrations in the lysosomal compartments of myeloid cells. In vitro analyses indicated that B. anthracis bacilli were sensitive to the antimicrobial activities of cathelicidins at micromolar concentrations. Cathelicidin administration caused increased neutrophil recruitment to the site of injection, reduced spore burden in Mac-1 positive cells, and increased mouse survival following subcutaneous spore challenge. However, no differences in survival were observed between cathelicidin-deficient and wild-type control mice following s.c. spore challenge. Cumulatively, these results suggest that cathelicidin expression does not contribute to host defense during an anthrax infection, but might be beneficial if administered exogenously. Additional experiments will be required to elucidate how B. anthracis evades the bactericidal activity of cathelicidins in vivo as well as to further characterize the therapeutic potential of cathelicidin administration during an anthrax infection.
Recommended Citation
Lisanby, Mark W., "Examination of the Capacity of the Cathelicidins to Control Bacillus Anthracis Pathogenesis" (2009). All ETDs from UAB. 230.
https://digitalcommons.library.uab.edu/etd-collection/230