Current understanding of Bacillus anthracis toxin molecules organization and approaches for blocking their cytotoxic action

Abstract

Here, we review the data on mechanisms inhibiting cytotoxic effect of anthrax toxin on the immune system cells. Various disease forms, immunopathogenesis and contemporary methods for anthrax treatment are discussed. In addition, an anthrax toxin was outlined, whereas structural and functional organization of the protective antigen, lethal and edema factors was detailed. A mechanism for association of a protective antigen and lethal factor, protective antigen and edema factor leading to formation of a lethal toxin and edema toxin, respectively, was described. Participation of protective antigen domains in the process of interaction with surface receptors of imunocompetent cells as well as features of binding a protective antigen with lethal factor and edema factor are discussed. A mechanism of endosomal toxin complex internalization and subsequent transfer of effector molecules to the cytosol are described. Effects of the lethal factor and the edema factor on components of eukaryotic cells as well as cytotoxicity mechanisms are analyzed. The approaches to block anthrax toxin action at various stages of toxicoemia have been analyzed based on previously uncovered sequential signs of cytotoxic activity for Bacillus anthracis toxins. Currently available chimeric and humanized monoclonal antibodies are capable of neutralizing B. anthracis toxins at diverse assembly stages, particularly considering the drugs inhibiting: inter-receptor interaction between protective antigen with eukaryotic cells; furin-like enzymes activating prepore assembly; protective antigen oligomerization; binding of the lethal factor or edema factor to the protective antigen; translocation of the lethal factor or the edema factor into cell cytosol; transport of protective antigen with lethal factor or edema factor from endosomes; enzymatic activity of lethal factor or edematous factor. The anti-toxin agents approved for anthrax prevention and treatment in Russia and worldwide are discussed. The limitations of anti-toxin agents and perspectives for their improvement are also described including inhibition of lethal factor activity, interference with integration of toxin components, blockade of interactions between toxic complexes and immune cell receptors.

Mechanism of Action of Monoclonal Antibodies That Block the Activity of the Lethal Toxin of <i>Bacillus Anthracis</i>

“…With changes in the environment’s pH level, PA changes its conformation, penetrates into the endosome, and forms a true pore for LF/EF translocation into the cytosol [ 9 ]. LF is a zinc metalloprotease that cleaves mitogen-activated protein kinase kinases (MAPKs) in the cytosol, which ultimately leads to cell apoptosis [ 10 , 11 ]. Figure 1 presents all assembly stages and the toxic activity of LT and ET from B. anthracis as well as the key stages of the antitoxic activity of the monoclonal antibodies that specifically interact with the Bacillus anthracis protective antigen domain IV.…”

“…They are used as targeted agents for the elimination of pathological cells [ 14 , 15 ]. Antibodies are very actively used as protective agents in toxic infections [ 11 , 16 , 17 ].…”