Anthrax Protective Antigen PA

Anthrax, a disease caused by infection by Bacillus anthracis via spores, can be transmitted to humans or animals ruminants such as sheep, goats, cattle, and deer are most susceptible. The handling of infected animals or animal products may also lead to human infection. Recently, anthrax has been considered to be a potential candidate for bioterrorism activity. The spores are extremely hardy and may come into contact with humans through a cut or abrasion, through consumption of infected meat, or by inhalation. The Center for Disease Control (CDC) lists anthrax as a category A disease, and the only vaccine that currently exists has a number of drawbacks and health risks. 

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One of the early investigations of cellular metabolism in the MAMP concerned the discrimination of select list agents based on resulting changes in cellular metabolism upon exposure. The metabolic profiles of neuroblastoma, macrophage, and kidney cell lines exposed to ricin, botulinum neurotoxin, cholera toxin (CTx), muscarine, alamethicin and anthrax protective antigen (PA) were performed [22], and each presented... 

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 anthrax bioterrorist attacks that followed the events of September 11th 2001 resulted in a renewed interest BadUus anthracis, the causative agent of this disease. Research has focused on the development of better vaccines than the one currently available. It has been estimated that the aerosolized release of 100 kg of anthrax spores upwind of Washington DC would cause mortalities of 130,000-3,000,000 [63]. Nonetheless, wild-type Bacillus anthracis is susceptible to conventional antibiotics, including penicillin, oxyfloxacin and ciprofloxacin. The problem lies not with the bacterial infection itself, but with three proteins released by the bacteria - protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa) and edema factor (EF, 89 kDa) -known as anthrax toxins [63]. 

Anthrax Anthrax is a toxin with three separate components a protective antigen (PA), an edema factor (EF), and a lethal factor (LF). 

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]. 

Anthrax toxin is composed of three proteins protective antigen (PA 83kDa), lethal factor (LF 90kDa), and edema factor (EF 89kDa). Individually, none of the three proteins are toxic but interact synergistically with at least one of the others. PA and LF (called LeTx) can cause lethal shock in experimental animals, and a mixture of PA and EF (edema toxin, EdTx) induces edema at the site of injection. Since two discrete units of the toxin are required for its action, the term binary toxin has been used to this and other bacterial toxins. Anthrax is unique from other binary toxins in that the binary moieties (EF and LF) interact only after being secreted from the bacteria. Further, EF and LF enter the cell via a single PA protein. Assembly of the three toxin proteins is initiated when PA binds to a proteinaceous cellular receptor and is activated by a member of the furin family of cellular proteases. The exact mechanisms of internalization of the toxin moieties are subject of scientific enquiry. Inside the cellular cytoplasm, EF (a calcium and calmodulin-dependent adenylate cyclase) causes a dramatic increase in intracellular cAMP concentrations and LF acts proteolytically to cleave certain MAPK kinases. 

Edema Toxin (EdTx) and Lethal Toxin (LeTx) are two toxins with immunomodulatory activity that are produced by A anthracis, the cause of the disease anthrax. Both toxins are composed of a heptameric complex of protective antigen (PA) bound to either edema factor (EF) or lethal factor (LF). " The heptameric complex of PA is responsible for receptor binding and cellular entry, whereas toxicity is associated with both EF, a calmodulin-dependent adenylate cyclase that induces increases in cytosolic cAMP and LF, a metalloprotease that cleaves mitogen-activated protein kinase kinases (MAPKK). ... 

Corbett, J. T., Kende, M., Kline, J. D., AUan, J. M., Lake, R. A., Yan, C. and Shalaby, S. W., Controlled release of recombinant protective antigen (r-PA) form of anthrax vaccine. Sixth World Biomaterials Congress, Trans Soc. Biomater., II, 766,2000. 

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