Lethal toxin actions and their consequences

After entry of infectious anthrax spores into the body, host-specific signals induce spore germination, outgrowth of vegetative bacilli and the expression of lethal toxin and other virulence factors. Anthrax lethal toxin (LeTx) is a virulence factor responsible for the major pathologies seen during systemic anthrax infections. Injection of sterile LeTx into test animals mimics the shock and sudden death seen during active bacterial infections. Once large levels of LeTx are produced within the body, destruction of bacteria by administration of antibiotics is usually unsuccessful. The LeTx is believed to be secreted into the bloodstream where it circulates freely throughout the body and binds and enters host cells. Once in the cytoplasm, the lethal factor acts as a zinc-metalloprotease disrupting normal homoeostatic functions. Macrophages are a uniquely sensitive cell type that seem to be vital global mediators of toxin-induced pathologies. Removal of macrophages from mice renders them insensitive to LeTx challenge. Low levels of lethal toxin induce macrophage production, in vitro, of the shock-inducing cytokines TNF and Il-1beta. Higher levels of LeTx cause over-production of reactive oxygen intermediates, bursting of macrophages and release of mediators of shock. We believe that agents capable of blocking key steps of the lethal toxin cascade may prove useful in combating anthrax pathologies.