The overall objective of this program project is to provide sufficient understanding of the mechanisms of Bacillus anthracis spore-host interactions to facilitate the design and development of preventive, interventive and diagnostic procedures for the disease Anthrax. We will determine the detailed chemical structure of glycoproteins and other spore coat determinants and investigate the possibility that they can be used as new B. anthracis spore-specific targets for anthrax prevention and treatment. The detailed composition of the exosporium will be characterized by genetic and biochemical strategies. Individual mutations of all known, and to be discovered, exosporium components will be made. The structure of the carbohydrate components of the exosporium will be determined using a variety of genetic, chemical and spectroscopic methods. A mouse model will be used to identify the cellular pathways of spore entry and passage via the airways, gastrointestinal, cutaneous, and blood routes. Mice in which selected genes of the innate and adaptive immune system have been inactivated by gene-targeting will be used to define mechanisms of immunopathology and immune evasion of the ungerminated spores in the host. Wild type and mutant spores will be used to determine the role of these components in spore integrity, spore germination and survival in a mammalian host. We will isolate and characterize spore-receptors on host cells using spores, recombinant exosporium components and defined carbohydrates as ligands for these receptors. In addition, this project will also involve the construction of carbohydrate-protein conjugates and neoglycoproteins designed on the basis of our structural studies. These constructs, in addition to cloned and expressed recombinant exosporium proteins, will be used to enhance immune responses to the glycoconjugates on the exosporium of B. anthracis, and assist in the development of novel vaccine or interventional strategies that will optimize specific protective primary and secondary immune responses, and may lead to new strategies for blockade of spore entry into the host. Our overall strategy differs from that currently in use which is designed to induce protective immunity to the toxins elaborated by the vegetative form of B. anthracis after spore invasion and germination in the host. We will be able to identify potential mechanisms to rapidly inactivate spores prior to establishment of infectious loci and vegetative cell outgrowth. Therapeutic drugs of this nature would be a major supplement to the current recommended antibiotic regimens or in the case of multidrug-resistant B. anthracis strains engineered to produce additional toxins for use as bioweapons.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Study Section
Special Emphasis Panel (ZAI1-SR-M (M1))
Program Officer
Baker, Phillip J
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University of Alabama Birmingham
Schools of Medicine
United States
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Tan, Li; Li, Mei; Turnbough Jr, Charles L (2011) An unusual mechanism of isopeptide bond formation attaches the collagenlike glycoprotein BclA to the exosporium of Bacillus anthracis. MBio 2:e00084-11
McPherson, Sylvia A; Li, Mei; Kearney, John F et al. (2010) ExsB, an unusually highly phosphorylated protein required for the stable attachment of the exosporium of Bacillus anthracis. Mol Microbiol 76:1527-38
Tan, Li; Turnbough Jr, Charles L (2010) Sequence motifs and proteolytic cleavage of the collagen-like glycoprotein BclA required for its attachment to the exosporium of Bacillus anthracis. J Bacteriol 192:1259-68
Dong, Shengli; McPherson, Sylvia A; Wang, Yun et al. (2010) Characterization of the enzymes encoded by the anthrose biosynthetic operon of Bacillus anthracis. J Bacteriol 192:5053-62
Yu, Cuiling; Ehrhardt, Götz R A; Alder, Matthew N et al. (2009) Inhibitory signaling potential of a TCR-like molecule in lamprey. Eur J Immunol 39:571-9
Oliva, Claudia; Turnbough Jr, Charles L; Kearney, John F (2009) CD14-Mac-1 interactions in Bacillus anthracis spore internalization by macrophages. Proc Natl Acad Sci U S A 106:13957-62
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Dong, Shengli; Chesnokova, Olga N; Turnbough Jr, Charles L et al. (2009) Identification of the UDP-N-acetylglucosamine 4-epimerase involved in exosporium protein glycosylation in Bacillus anthracis. J Bacteriol 191:7094-101
Lisanby, Mark W; Swiecki, Melissa K; Dizon, Brian L P et al. (2008) Cathelicidin administration protects mice from Bacillus anthracis spore challenge. J Immunol 181:4989-5000
Dong, Shengli; McPherson, Sylvia A; Tan, Li et al. (2008) Anthrose biosynthetic operon of Bacillus anthracis. J Bacteriol 190:2350-9

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