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One of the key causes of anthrax virulence is the action of three specific factors produced by the bacterium Bacillus anthracis. Even with successful antibiotic treatment, anthrax toxins can remain in the circulation and cause lethality. The toxins produced by anthrax bacteria are lethal factor (LF), protective antigen (PA) and edema factor (EF). The entry of toxin into cells begins with the recognition of a 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. (This definition may be outdated - see the DesignNote.)
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