Anthrax Toxin

Abstract

Anthrax toxin consists of three nontoxic proteins that associate in binary or ternary combinations to form toxic complexes at the surface of mammalian cells. One of these proteins, protective antigen (PA), transports the other two, edema factor (EF) and lethal factor (LF), to the cytosol. LF is a Zn2+-protease that cleaves certain MAP kinase kinases, leading to death of the host via a poorly defined sequence of events. EF, a calmodulin- and Ca2+-dependent adenylate cyclase, is responsible for the edema seen in the disease. Both enzymes are believed to benefit the bacteria by inhibiting cells of the host's innate immune system. Assembly of toxic complexes begins after PA binds to cellular receptors and is cleaved into two fragments by furin proteases. The smaller fragment dissociates, allowing the receptor-bound fragment, PA63 (63 kDa), to self-associate and form a ring-shaped, heptameric pore precursor (prepore). The prepore binds up to three molecules of EF and/or LF, and the resulting complexes are endocytosed and trafficked to an acidic compartment. There, the prepore converts to a transmembrane pore, mediating translocation of EF and LF to the cytosol. Recent studies have revealed (a) the identity of receptors; (b) crystallographic structures of the three toxin proteins and the heptameric PA63 prepore; and (c) information about toxin assembly, entry, and action within the cytosol. Knowledge of the structure and mode of action of the toxin has unveiled potential applications in medicine, including approaches to treating anthrax infections.

Patterns of antibody response in humans to the anthrax vaccine adsorbed (AVA) primary (six-dose) series☆

“…Two principal B. anthracis toxin components, lethal factor (LF, a Zn 2+ -protease) and edema factor (EF, a calmodulin-and Ca 2+ -dependent adenylate cyclase) are enzymes transported into cells by a third polypeptide, PA; combinations of PA with LF and EF yield B. anthracis lethal toxin (LT) and B. anthracis edema toxin (ET), respectively, that function as bacterial virulence factors in producing many of the symptoms of anthrax [13][14][15][16][17][18]. The pivotal role played by PA in toxin cell entry forms the basis for the current licensed anthrax vaccine, AVA (Biothrax TM ), a sterile culture filtrate of avirulent, non-encapsulated, B. anthracis (stimulated to produce relatively large amounts of PA) mixed with formalin and benzethonium chloride, and combined with aluminum hydroxide [19].…”

“…Samples were retrieved from −70 • C storage that met preestablished criteria: (a) Vaccinations must have occurred within defined time intervals after receipt of the initial AVA injection (day 0 [dose #1], day 14 [range [11][12][13][14][15][16][17][18][19][20][21] ). (b) Pre-injection sera were defined as those taken on the day of each vaccine dose.…”

Quantitative analysis of the effect of cell type and cellular differentiation on protective antigen binding to human target cells

“…PA-mediated internalization of LF and EF occurs following PA heptamerization on the cell surface and pH-dependent pore formation within the endosome (reviewed in [2]). Quantification of the affinity and number of endogenous PA-specific receptors is important for understanding the role of PA in anthrax virulence and its potential as a pharmaceutical delivery agent [3][4][5].…”

Natural Exposure to Cutaneous Anthrax Gives Long-Lasting T Cell Immunity Encompassing Infection-Specific Epitopes

“…PA consists of four domains, the proteolytic cleavage of an exposed loop in the 20-kDa N-terminal domain causes the release of this domain, and the spontaneous oligomerization of truncated PA into heptamers that bind to EF and LF, to form edema toxin (ET) and lethal toxin (LT), respectively (5,6). PA binds the widely expressed, host cell-surface receptors, tumor endothelium marker 8, and capillary morphogenesis protein 2 (7,8).…”