Anthrax function

The anthrax toxin is a tripartite toxin and consists ofthe binding component protective antigen (PA), the lethal factor (LF), which is a metalloprotease, and the edema factor (EF), which is a calmodulin-dependent adenylyl-cyclase. Both enzyme components are translocated via PA into target cells. PA is activated by furin-induced cleavage and forms heptamers, which are similar to the binding components of C2 toxin and iota toxin. In the low pH compartment of endosomes, the heptamers form pores to allow translocation of LF and EF. LF cleaves six of the seven MEKs (MAPK-kinases) thereby inhibiting these enzymes. The functional consequence is the blockade of the MAPK pathways that control cell proliferation, differentiation, inflammation, stress response, and survival. Whether this is the reason for the LT-induced cell death of macrophages is not clear [1]. 

The LF is the most disruptive to cellular functions and disables intracellular signaling molecules. It prevents macrophages from releasing tumor necrosis factor (TNF) and interleukin cytokines, although the production of TNF and cytokines in the macrophages is not impeded. The host s immune system is compromised and is unable to eliminate the anthrax bacillus. 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

Anthrax toxin is a bacterial toxin from Bacillus anthracis consisting of three parts protective antigen (PA), lethal factor (LF) and edema factor (EF). Both LF and EF compete for binding sites on the PA protein. The PA protein binds with high affinity to an as yet unknown receptor on macrophages and related cell types. When PA is internalized by the target cells, it functions as a shuttle protein for either EF or LF. Intracellularly, in the acidic environment of the endosome, EF and LF are capable of entering the cytosol by pH-dependent pore formation [139]. 

The same amidation reaction was employed by Joshi et al. to covalently functionalize MWNTs with a specific peptide sequence, which specifically binds to the heptameric receptor-binding subunit of anthrax toxin.33 These nanotube-peptide conjugates were found to selectively destroy anthrax toxin with the reactive oxygen species generated by the nanotubes upon near-IR radiation.33... 

Figure 6.2 The Ca2+-mediated aggregation of anthrax spores with sugar functionalized SWNTs (a) a schematic illustration (b) SEM image (scale bar = 500 nm) and (c) optical image (scale bar = 20 p.m).u (Reprinted with permission from H. Wang et al., J. Am. Chem. Soc. 2006, 128, 13364—13365.

Abalakin, V.A., Sirina, E.G., Cherkasova, T.D. (1990). The effect of lethal anthrax toxin on the functional activity of peritoneal mononuclear phagocytes and polymorphonuclear neutrophils in mice. Zh. Mikrobiol. Epidemiol. Immunobiol. 2 62-1. (In Russian)... 

Scobie, H.M., Rainey, G.J., Bradley, K.A., Young, J.A. (2003). Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. Proc. Natl Acad. Sci. USA 100 5170-4. 

Another example where the importance of affinity has been clearly highlighted is the protective function of antibodies against toxic or infectious agents. For example, post-challenge protection against the anthrax toxin, a tripartite protein, correlated well with the dissociation constant of the antibody, all other properties being equal [75]. 

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