| Notes: | Advisor: Dominique Missiakas.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences, and The Pritzker School of Medicine, Department of Microbiology, 2011.
Dissertation Abstracts International, Volume: 72-09, Section: B, page: 5091.
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| Summary: | Anthrax is an infectious disease caused by the bacterium Bacillus anthracis through three of routes of infection: cutaneous, pulmonary and gastrointestinal. Most commonly infecting grazing ruminants, B. anthracis is capable of infecting all mammals. Though the mortality of anthrax depends largely upon the host specie and primary inoculum, a hallmark of the disease is its quick progression. In humans, the onset of symptoms may occur several days in advance, while some animal hosts may succumb to infection having displayed no symptoms whatsoever.
A critical feature of the Bacillus anthracis life cycle is the bacterium's ability to sporulate. Endospores are metabolically-inert, non-reproductive forms the bacterium can produce in response to environmental stimuli. These spores serve to protect the bacterium from deleterious conditions until a new host is acquired. Importantly, the ability of spores to persist in the soil, coupled with the extreme susceptibility of grazing livestock, has rendered anthrax to be, arguably, one of the most important agricultural pathogens to date. Moreover, the ease of production and longevity of spores has been exploited on multiple occasions, making the anthrax bacillus one of the most notorious agents of biological warfare. Perhaps, however, the most important impact this microbe has levied on history is its role in the establishment of "Koch's postulates", on which rests the very foundation of modern microbiology. Indeed, the complexity of the Bacillus anthracis lifestyle, which scientists began to dissect almost 150 years ago, continues to be refined today.
In particular, the surface of B. anthracis has two major surface macromolecules that are requirements for virulence: a capsule and a surface layer. The capsule is a unique peptidic capsule consisting of long polymers of poly-gamma-D-glutamic acid that is covalently anchored onto the bacterial surface. The surface layer is a paracrystalline array of protein monomers that self-assemble in a non-covalent matrix surrounding the bacterium. While both structures have been addressed in the literature in multiple facets, a refined understanding of the molecular mechanisms governing the secretion and assembly of these important macromolecules is still lacking.
As such, this thesis is structured into six chapters. The first chapter provides an introduction to anthrax, split between a brief summary of anthrax disease and its study through human history and a basic description of the physiology of Bacillus anthracis pertaining to its surface macromolecules. The second chapter considers the B. anthracis capsule and seeks to explain the mechanism of capsular attachment to the peptidoglycan. The third chapter describes patterns of surface layer assembly and considers the secretion requirements required for surface layer elaboration. The fourth chapter describes the discovery of an enzyme associated with the surface layer that controls bacterial chain length. The fifth chapter attempts to demonstrate the dependence of the localization of the chain-dispersing enzyme to the presence of an intact surface layer, which we ultimately propose may function as an indirect-targeting mechanism for select envelope proteins. The conclusion summarizes the findings in this thesis and offers ideas for future research efforts towards further resolution of the processes described herein.
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