Lethal toxin actions and their consequences

After entry of infectious anthrax spores into the body, host-specific signa ls induce spore germination, outgrowth of vegetative bacilli and the expres sion of lethal toxin and other virulence factors. Anthrax lethal toxin (LeT x) is a virulence factor responsible for the major pathologies seen during systemic anthrax infections. Injection of sterile LeTx into test animals mi mics the shock and sudden death seen during active bacterial infections. On ce large levels of LeTx are produced within the body, destruction of bacter ia by administration of antibiotics is usually unsuccessful. The LeTx is be lieved to be secreted into the bloodstream where it circulates freely throu ghout 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 cytok ines TNF and 11-1 beta. Higher levels of LeTx cause over-production of reac tive oxygen intermediates, bursting of macrophages and release of mediators of shock. We believe; that agents capable of blocking key steps of the let hal toxin cascade may prove useful in combating anthrax pathologies.