The Ins and Outs of Anthrax Toxin

Abstract

Anthrax is a severe, although rather rare, infectious disease that is caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. The infectious form is the spore and the major virulence factors of the bacterium are its poly-γ-D-glutamic acid capsule and the tripartite anthrax toxin. The discovery of the anthrax toxin receptors in the early 2000s has allowed in-depth studies on the mechanisms of anthrax toxin cellular entry and translocation from the endocytic compartment to the cytoplasm. The toxin generally hijacks the endocytic pathway of CMG2 and TEM8, the two anthrax toxin receptors, in order to reach the endosomes. From there, the pore-forming subunit of the toxin inserts into endosomal membranes and enables translocation of the two catalytic subunits. Insertion of the pore-forming unit preferentially occurs in intraluminal vesicles rather than the limiting membrane of the endosome, leading to the translocation of the enzymatic subunits in the lumen of these vesicles. This has important consequences that will be discussed. Ultimately, the toxins reach the cytosol where they act on their respective targets. Target modification has severe consequences on cell behavior, in particular on cells of the immune system, allowing the spread of the bacterium, in severe cases leading to host death. Here we will review the literature on anthrax disease with a focus on the structure of the toxin, how it enters cells and its immunological effects.

Anthrax protective antigen is a calcium-dependent serine protease

“…The entire receptor-toxin complex is then endocytosed and transported into low-pH endosomes. Triggered by the acidic environment a pore forms across the endosomal membrane, after which EF and LF are released into the cytosol of the host cell [5]. Once present in the cell cytosol, EF and LF damage the cell in various ways; LF is a zinc-dependent metalloproteinase that cleaves and inactivates the mitogen-activated protein kinase (MAPK) kinases 1–4, 6 and 7 [6].…”

Soluble P-selectin rescues mice from anthrax lethal toxin-induced mortality through PSGL-1 pathway-mediated correction of hemostasis

“…Lethal toxin (LT) is a major virulence factor and consists of 2 proteins, protective antigen (PA) and lethal factor (LF). 1 PA binds to specific cellular receptors and forms a membrane channel that mediates the entry of LF into target cells. 2 LF is a metalloprotease, which inhibits mitogen-activated protein kinase (MAPK) signaling pathways through the proteolytic inactivation of MAPK kinases (MEKs).…”

Human lung ex vivo infection models

“…Important virulence factors of B. anthracis include two toxins: both lethal toxin (LT) and edema toxin (ET) share the protective antigen (PA) as a common receptor-binding component. PA allows the transport of the catalytic components LF and EF into the cytosol of target cells (Friebe et al 2016;Moayeri et al 2015). Chakrabarty et al (2007) tested B. anthracis spore-related inflammatory tissue activation by utilizing spores prepared from the B. anthracis Sterne strain 7702(pX01 + , pX02 -).…”

“…An important unresolved question is: how do B. anthracis spores escape from the alveolar airspace into the systemic circulation (Friebe et al 2016;Moayeri et al 2015)? In principle, transport might occur via host cells used as Trojan horses (AM, dendritic cells [DC], or a hitherto unidentified Bcarrier^cell) or spores may cross the alveolar epithelial wall without the help of migratory cells.…”

“…In principle, transport might occur via host cells used as Trojan horses (AM, dendritic cells [DC], or a hitherto unidentified Bcarrier^cell) or spores may cross the alveolar epithelial wall without the help of migratory cells. Finally, a sequence of spore clustering, germination and production of B. anthracis virulence toxins has been proposed to cause epithelial damage that allows free spore passage (Friebe et al 2016;Goossens and Tournier 2015;Moayeri et al 2015), the so-called Bjailbreak^model (Weiner and Glomski 2012). By using the above-mentioned model (Chakrabarty et al 2007), the same group (Booth et al 2016) aimed to identify the role of carrier cells and of B. anthracis toxins in this process.…”