Bacillus anthracis produces a toxin that causes cell death and mortality in infected individuals. Even if the bacterial infection itself is controlled by antibiotics, an infected person often dies because the anthrax toxin (AT) produced in vivo by B. anthracis binds to human cells, is endocytosed, and kills the cells. Therefore development of specific antitoxins that prevent AT from binding to human cells is necessary for effectively treating anthrax exposure,. This is the goal of this Program Project grant. The groups of J. Young and J. Collier have discovered and characterized the interaction between AT and its cellular receptors. This work fuels the discovery and development of novel peptide-based anthrax anti-toxins (Projects 1 and 2). Here we propose to display the inhibitory peptides and soluble AT receptor-based proteins in a multivalent form using the plant virus particle cowpea mosaic virus (CPMV) or the insect virus Flock house virus (FHV) as display platforms (Projects 3-5). These multivalent platforms will be produced and tested for their efficacy as antitoxins both in vitro and in vivo. These viruses are heat and acid-stable and are easy to produce in large quantities. Both viruses have been very well characterized genetically, biochemically and structurally and can either be engineered, or chemically modified, to display multiple copies of foreign immunogenic or antitoxin peptide sequences on their surface. The Manchester group (project 3) has previously shown that a virus-cellular receptor interaction can be efficiently blocked, both in vitro and in vivo, by the multivalent display of an inhibitory peptide on CPMV. Using this exciting result as a proof of concept, we will test the hypothesis that multivalent display of AT inhibitory peptides on CPMV and FHV will lead to the creation of a panel of new and effective anthrax antitoxins and vaccine reagents.
| Schneemann, Anette; Manchester, Marianne (2009) Anti-toxin antibodies in prophylaxis and treatment of inhalation anthrax. Future Microbiol 4:35-43 |
| Venter, P A; Schneemann, A (2008) Recent insights into the biology and biomedical applications of Flock House virus. Cell Mol Life Sci 65:2675-87 |
| Strable, Erica; Prasuhn Jr, Duane E; Udit, Andrew K et al. (2008) Unnatural amino acid incorporation into virus-like particles. Bioconjug Chem 19:866-75 |
| Kaltgrad, Eiton; O'Reilly, Mary K; Liao, Liang et al. (2008) On-virus construction of polyvalent glycan ligands for cell-surface receptors. J Am Chem Soc 130:4578-9 |
| Scobie, Heather M; Marlett, John M; Rainey, G Jonah A et al. (2007) Anthrax toxin receptor 2 determinants that dictate the pH threshold of toxin pore formation. PLoS One 2:e329 |
| Manayani, Darly J; Thomas, Diane; Dryden, Kelly A et al. (2007) A viral nanoparticle with dual function as an anthrax antitoxin and vaccine. PLoS Pathog 3:1422-31 |
| Young, John A T; Collier, R John (2007) Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu Rev Biochem 76:243-65 |
| Sanchez, Ana M; Thomas, Diane; Gillespie, Eugene J et al. (2007) Amiodarone and bepridil inhibit anthrax toxin entry into host cells. Antimicrob Agents Chemother 51:2403-11 |
| Sun, Jianjun; Vernier, Gregory; Wigelsworth, Darran J et al. (2007) Insertion of anthrax protective antigen into liposomal membranes: effects of a receptor. J Biol Chem 282:1059-65 |
| Scobie, Heather M; Wigelsworth, Darran J; Marlett, John M et al. (2006) Anthrax toxin receptor 2-dependent lethal toxin killing in vivo. PLoS Pathog 2:e111 |
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