Anthrax Toxin Mechanism of Action
One of the key causes of anthrax virulence is the production of three specific factors by the gram-positive spore forming bacteria Bacillus anthracis. Even with successful antibiotic treatment, anthrax toxins can remain in the circulation and cause lethality. The toxins produced by anthrax bacteria are derived from three genes: lethal factor (LF), protective antigen (PA) and edema factor (EF). The entry of toxin into cells begins with the recognition of a recently identified cellular receptor in the plasma membrane by PA. Proteolytic cleavage of cell-bound PA creates a smaller fragment that then multimerizes into a pore-like structure in the plasma membrane. The LF and EF proteins bind to the PA pre-pore, followed by internalization of the entire structure through receptor-mediated endocytosis. In the endosomal compartment, the acidic pH causes a conformational change that inserts PA fragments and releases LF and EF into the cytoplasm. In the cytoplasm, LF acts as a protease that cleaves MAP kinase kinase (MAPKK 1 and MAPKK 2), inhibiting pathways that rely on this kinase family and causing cell death. Edema factor is an adenylate cyclase that inhibits the immune response, including phagocytosis by macrophages. Several potential mechanisms could be used to block anthrax toxin action, one of which was demonstrated by the design of a multivalent protein inhibitor of toxin interaction with PA.
Contributor: Glenn Croston, PhD
REFERENCES: Beauregard, K.E., Collier, R.J., Swanson, J.A. Proteolytic activation of receptor-bound anthrax protective antigen on macrophages promotes its internalization. Cell. Microbiol. 2000, 2(3), 251-8 Bradley, KA. et al. Identification of the cellular receptor for anthrax toxin. Nature 2001, 414(6860), 225-9 Duesbery, N.S. et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 1998, 280(5364), 734-7 Leppla, S.H. Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells. Proc. Natl. Acad. Sci. U. S. A. 1982, 79(10), 3162-6 Mourez, M. et al. Designing a polyvalent inhibitor of anthrax toxin. Nat. Biotechnol. 2001, (10), 958-61
