Abstract
Edema toxin (ET), which is composed of a potent adenylate cyclase (AC), edema factor (EF), and protective antigen (PA), is one of the major toxicity factors of Bacillus anthracis. In this study, we introduced mutations in full-length EF to generate alanine EF(H351A) and arginine EF(H351R) variants. In vitro activity analysis displayed that the adenylyl cyclase activity of both the mutants was significantly diminished compared with the wild-type EF. When the native and mutant toxins were administered subcutaneously in a mouse footpad edema model, severe acute swelling was evoked by wild-type ET, while the symptoms induced by mutant toxins were very minor. Systemic administration of these EF variants caused non-lethal hepatotoxicity. In addition, EF(H351R) exhibited slightly higher activity in causing more severe edema than EF(H351A). Our findings demonstrate that the toxicity of ET is not abolished by substitution of EF residue His351 by alanine or arginine. These results also indicate the potential of the mouse footpad edema model as a sensitive method for evaluating both ET toxicity and the efficacy of candidate therapeutic agents.
Highlights
Bacillus anthracis is a highly pathogenic bacterium that is the causative agent of anthrax, an acute infectious disease that is lethal to both humans and animals
Circular dichroism profiles indicate that the mutant proteins do not exhibit any gross structural differences compared to the wild-type edema factor (EF) [8] and remain competent in binding to protective antigen (PA) [13]
These increased such there between was no significant difference between the effects of the wild‐type and results indicate that3d,e). The sensitivity of this mousethat footpad edema model is sufficient to distinguish. These results indicate the sensitivity of this mouse footpad edema weak toxicity of EF(H351R)
Summary
Bacillus anthracis is a highly pathogenic bacterium that is the causative agent of anthrax, an acute infectious disease that is lethal to both humans and animals. The EF helical domain binds to the N-terminal domain of CaM, allowing insertion of the. C-terminal between the catalytic core and helical domains of EF This initiates a conformational change, in which the critical catalytic loop of EF with high AC activity (approximately 1000–2000 molecules per second) is stabilized through the switch C region [6]. EF was found to deplete cellular ATP, upregulate toxin receptors [10], and bind to other nucleotide triphosphates as substrates [11]. The existence of these other mechanisms underlying EF function demonstrates that candidate therapeutic agents cannot be identified on the basis of AC repression alone. Observation of the pathogenesis of edema indicated the potential of this model for the assessment of therapeutic candidates
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