Advisory Committee Chair
John F Kearney
Advisory Committee Members
Charles L Turnbough Jr
David D Chaplin
David E Briles
William H Benjamin
Zdenek Hel
Document Type
Dissertation
Date of Award
2015
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Bacillus anthracis (Ba) is a Gram,-positive zoonotic bacterium that causes inhala- tional, cutaneous and intestinal Anthrax Disease. Although the infectious form of Ba is its endospore (spore), only the tripartite toxin-producing vegetative bacteria causes disease pathology. While current vaccination strategies target the Protective Antigen (PA) com- ponent of this toxin, vaccine-elicited immunity to the spore form of Ba is lacking. How- ever, vaccines targeting spore components of Ba have the potential to neutralize the in- fectious form of Ba. We sought to determine if antibodies elicited through immunization with the main antigenic component of the spore surface- Bacillus collagen-like protein of Anthracis (BclA)- can mediate immunity and protect against lethal Ba infection. The study of Ba is problematic due to its inherent virulence and bio-safety con- cerns. Many laboratories utilize the Sterne strain, which only require a BSL II facility, but limits researchers to the susceptible A/J or similar mouse strains. In our initial studies we confirm that C5 deficiency renders C57BL/6 mice susceptible to this strain. Because the majority of genetically manipulated mice are on the C57BL/6 background, the use of C5 deficient mice (C5-/-) in the C57BL/6 background broadens our ability to study Ba- host interactions under a variety of experimental conditions. Intranasal immunization with recombinant BclA and cholera toxin provided sig- nificant protection from lethal intratracheal Ba challenge to complement component 5- deficient (C5-/-) C57BL/6 mice. Importantly, passive transfer of BclA-specific monoclo- ii nal antibodies (mAbs) was similarly able to protect from lethal Ba challenge, and signifi- cantly increase spore uptake by macrophages and lead to enhanced spore-destruction in vitro. The effects of BclA-specific mAbs are mediated by Fc receptors, which promoted endo-lysosomal fusion, increased acidification of the endosomal compartment, and sub- sequently promoted spore destruction within macrophages. Collectively, these results indicate that vaccine-elicited antibodies targeting the Ba spore component BclA can lead to protection from infectious Ba spores by promoting their uptake and destruction. BclA-targeted immunity could be a major supplement to current toxin-based vaccines. Furthermore, BclA-specific mAbs represent an important addition to current antibiotic regimens used to treat Ba, and may be of highly significant value in the treatment of multiple antibiotic-resistant Ba strains or bioengineered strains.
Recommended Citation
Rodriguez Barrantes, Juan Bosco, "Bcla As An Adjunct To Current Bacillus Anthracis Vaccination And Therapy Protocols" (2015). All ETDs from UAB. 2850.
https://digitalcommons.library.uab.edu/etd-collection/2850