Anthrax lethal toxin (LeTx) is an important component of the pathogenesis caused by Bacillus anthracis infections. We have recently identified mutations in a kinesin gene (Kif1 C) that increase susceptibility of mouse macrophages to the cytotoxic effects of LeTx. While it is well known that Kif1 C is a motor protein that mediates the intracellular transport of vesicles, the exact functions of Kif1 C in cells under normal and LeTx-intoxicated conditions are not well described. Accordingly, in the first 2 Aims, we propose experiments that exploit the different alleles of Kif1 C to try to unravel important aspects of its function. Specifically, we will test if the susceptibility-inducing mutations affect Kif1 C protein abundance, the susceptibility of Kif1 C to LF mediated proteolysis, the intracellular distribution or phosphorylation of Kif1 C, and the interactions of Kif1 C with likely cargo vesicles and proteins. The third Aim is designed to explore some essential unexplained questions about the functioning of the anthrax toxins during anthrax pathogenesis. We propose to investigate the possibility of an interaction between edema toxin and lethal toxin in the cytolysis of macrophages. We also propose to search for human macrophage variation in LeTx susceptibility as a means to better understand the pathogenesis of human anthrax and perhaps provide an explanation of variation in human susceptibility to anthrax.