Bacillus anthracis lethal toxin and edema toxin modify the physiology of cells by disrupting MAPKK signaling pathways and causing accumulation of cAMP respectively. Both MAPKK signaling and cAMP are important regulators of development and exposure of embryos to anthrax toxin could lead to defects. In recent DNA array studies we have found that Wnt signalling may also be disrupted by lethal toxin. Wnt signaling is a major part of development and aberrations in this pathway could also lead to defects in the developing embryo. In light of these observations we carried out pilot experiments on zebrafish embryos and found noticeable defects after treatment with anthrax toxin. These results strongly suggest a better understanding of anthrax toxin's impact on development is needed. In the case of a bioterrorist disseminating B. anthracis spores over a populated area, at least 1.5% of the human population will be pregnant and embryos could be exposed to the toxin. Therefore, in order to better understand the impact of anthrax toxin on embryonic development, we will address two specific aims. Specific Aim 1. We will determine the impact lethal toxin and edema toxin have on zebrafish embryo development. Specific Aim 2. We will determine the impact inactive anthrax toxin mutants have on zebrafish embryo development. Specific aim 2 will address the possibility that vaccine and therapeutic candidates might cause developmental defects.

R21HD044861

2003-08-01

2006-07-31