Friday, May 9, 2008

Genetic Approaches to Study Host-Pathogen Interactions in Anthrax
Ken Bradley
Professor of Microbiology
Department of Microbiology, Immunology & Molecular Genetics

Virulence of B. anthracis, the causative agent of anthrax, is associated with the secretion of two toxins: lethal toxin (LT), and edema toxin (ET). In order to better understand the role of these toxins, we study the molecular processes and host genes that are required for them to efficiently interact with host cells.  Our first approach, somatic cell genetic screening, led to the identification of two anthrax toxin receptors (ANTXRs) that are required for both LT and ET to interact with host cells 1. The second approach involves genetic screens in mice, which have led to the identification of at least one host gene that contributes to a very rapid response to LT (unpublished). The third approach is based on “chemical genetics”, which is the testing of tens of thousands of drug-like small molecules for their ability to alter biological processes. This approach serves two goals, as small molecules that are found to block LT interactions can be used to study the biology of toxin-host interactions, but can also be used as starting points for development of therapeutics to treat anthrax 2.

1.            Bradley, K. A., Mogridge, J., Mourez, M., Collier, R. J. & Young, J. A. Identification of the cellular receptor for anthrax toxin. Nature 414, 225-9 (2001).
2.            Sanchez, A. M. et al. Amiodarone and bepridil inhibit anthrax toxin entry into host cells. Antimicrob Agents Chemother 51, 2403-11 (2007).