The recent anthrax-related events have revealed the need to fill gaps in the knowledge base that compromise our response to a bioterrorist attack using Category A pathogens like Bacillus anthracis. As with most biological systems, there is tremendous diversity in response to pathogens. This SBIR Phase I project will test for diversity in host response to anthrax lethal toxin (LeTx). The investigators will identify and incorporate this diversity into a PathoGenix panel to: (1) mimic a genetically diverse, human population as the target in a bioterrorist attack; (2) be used as a sensitive screen for susceptible genotypes; and (3) identify intracellular pathways for therapeutic intervention. First, candidate rat strains will be selected based on the haplotype of anthrax-related genes using in silico tools. Second, in vivo and in vitro susceptibility to anthrax LeTx will be quantified followed by establishment of combinatorial breeding pairs. Third, the effects of LeTx will be measured in the panel, which enables localization of the gene region responsible for resistance or susceptibility. Decoding these data will begin to define the genomic contribution of the host-pathogen relationship. The goal in this project is to validate a new panel of rats for detecting the genetic effects of anthrax LeTx.
