- The anthrax toxin is the primary virulence factor of Bacillus anthracis, responsible for much of the tissue damage, immune suppression, and lethality associated with anthrax disease.
- It is an exotoxin composed of three distinct proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). Each component is individually non-toxic, but together they form binary toxin complexes that disrupt host cell function. PA is the binding and delivery component, while LF and EF are the enzymatic effectors. The coordinated action of these proteins enables the bacterium to evade immune defenses, damage host tissues, and cause systemic pathology.
- Protective antigen (PA) plays a central role in toxin entry. After binding to anthrax toxin receptors on the host cell surface—mainly TEM8 (tumor endothelial marker 8) and CMG2 (capillary morphogenesis protein 2)—PA is cleaved by host proteases into an active 63-kDa fragment. This fragment oligomerizes into a heptamer or octamer, forming a prepore structure that serves as a docking platform for LF and EF. The PA oligomer, along with its bound LF or EF, is internalized by receptor-mediated endocytosis. Acidification of the endosome triggers conformational changes in PA, leading to pore formation and the translocation of LF and EF into the host cytosol.
- Lethal factor (LF) is a zinc-dependent metalloprotease that specifically cleaves mitogen-activated protein kinase kinases (MAPKKs), a family of key signaling proteins involved in cell growth, immune response, and stress regulation. By disrupting MAPK signaling, LF impairs immune cell function, promotes apoptosis in macrophages, and contributes to systemic immune suppression. This activity is central to the rapid disease progression and high mortality associated with inhalational anthrax. In combination with PA, LF forms “lethal toxin,” which is highly cytotoxic and responsible for shock-like symptoms in severe anthrax cases.
- Edema factor (EF) is a calmodulin-dependent adenylate cyclase enzyme. Once inside the cytosol, it converts ATP to cyclic AMP (cAMP) at abnormally high levels, leading to disruption of cellular signaling, fluid imbalance, and impaired immune responses. Elevated cAMP weakens neutrophil function, prevents effective phagocytosis, and causes fluid accumulation in tissues. In combination with PA, EF forms “edema toxin,” which contributes to massive swelling (edema) and tissue necrosis seen in cutaneous and gastrointestinal anthrax.
- The combined activity of lethal toxin and edema toxin creates a powerful dual assault on the host. Lethal toxin primarily damages and kills immune cells, while edema toxin prevents effective immune responses and promotes tissue destruction. Together, they establish an environment favorable to bacterial survival and systemic spread, ultimately leading to septicemia, shock, and death if untreated.
- The importance of anthrax toxin in disease has made it a major target for medical countermeasures. The anthrax vaccine primarily induces antibodies against protective antigen, blocking the entry of LF and EF into host cells. In addition, monoclonal antibody therapies such as raxibacumab and obiltoxaximab have been developed to neutralize PA, preventing toxin entry and offering adjunctive treatment alongside antibiotics. These therapies underscore the central role of anthrax toxin in pathogenesis and the necessity of targeting it for effective medical intervention.
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