Anthrax lethal and edema toxins in anthrax pathogenesis

Abstract

The pathophysiological effects resulting from many bacterial diseases are caused by exotoxins released by the bacteria. Bacillus anthracis, a spore-forming bacterium, is such a pathogen, causing anthrax through a combination of bacterial infection and toxemia. B. anthracis causes natural infection in humans and animals and has been a top bioterrorism concern since the 2001 anthrax attacks in the USA. The exotoxins secreted by B. anthracis use capillary morphogenesis protein 2 (CMG2) as the major toxin receptor and play essential roles in pathogenesis during the entire course of the disease. This review focuses on the activities of anthrax toxins and their roles in initial and late stages of anthrax infection.

Keywords: anthrax; capillary morphogenesis protein 2; edema toxin; lethal toxin; tumor endothelial marker 8.

Figure 1

Mode of action of anthrax toxins. Following secretion by B. anthracis, the anthrax toxin components distribute quickly into various tissues. Upon binding to cell-surface receptors, PA is cleaved by furin or furin-like proteases, yielding the C-terminal fragment PA₆₃ (dashed arrows), which then spontaneously forms oligomers that gain the ability to bind LF and EF. PA can also be processed in circulation by unidentified proteases, and the resulting PA₆₃ can oligomerize and bind LF and EF prior to binding to the toxin receptors CMG2 and TEM8 to form the PA₆₃ oligomer-receptor complex. CMG2 is the major toxin receptor in vivo, whereas TEM8 plays only a minor role in anthrax toxin pathogenesis. The toxin complex is then internalized through the receptor-mediated endocytosis. Once inside endosomes, the toxin complex encounters an acidic environment, which induces the formation of the PA₆₃ oligomer channel in the membrane, allowing LF and EF to enter the cytosol to exert their cytotoxic effects.

Figure 2

The roles of anthrax toxins in infection. Upon entering a host through various routes, B. anthracis spores may germinate locally or be carried to local lymph nodes and germinate there. The vegetative bacteria then secrete lethal toxin (LT = PA + LF) and edema toxin (ET = PA + EF), which act through binding to CMG2 receptors to incapacitate the scavenger functions of myeloid cells (such as neutrophils and macrophages). This allows the expanding population of vegetative bacteria to evade the powerful anti-bacterial functions of neutrophils and macrophages. At late stages, following dissemination and establishment of a systemic infection, B. anthracis multiplies to high numbers in the blood, producing sufficient amounts of LT and ET to cause host mortality. LT causes host lethality through targeting the cardiovascular system, in particular cardiomyocytes and vascular smooth muscle cells, whereas ET induces lethality mostly by targeting hepatocytes.