Bacillus anthracisEdema Toxin InhibitsStaphylococcus aureusEnterotoxin B Effects In Vitro: a Potential Protein Therapeutic?

Abstract

Various in vitro effects of staphylococcal enterotoxin B (SEB) on human peripheral blood mononuclear cells were mitigated by Bacillus anthracis edema toxin. In particular, levels of some SEB-induced cytokines (tumor necrosis factor alpha, gamma interferon) and chemokines (monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha [MIP-1␣], MIP-1␤) were significantly diminished or even nonexistent, depending upon the timing of edema toxin administration. Overall, these results suggest a novel use of B. anthracis edema toxin against a bacterial superantigen.Bacillus anthracis and Staphylococcus aureus are gram-positive pathogens involved in numerous human/animal diseases that include skin-linked maladies such as cutaneous anthrax, carbuncles, impetigo, and scalded-skin syndrome (16,35). The various protein toxins produced by these bacteria (i.e., B. anthracis lethal toxin or S. aureus enterotoxins/toxic shock syndrome toxin 1) can profoundly affect a host in multiple ways, which may result in morbidity, shock, and even death. Furthermore, B. anthracis and staphylococcal enterotoxin B (SEB) are considered by the Centers for Disease Control and Prevention to be select agents that warrant monitoring by the federal government. Therefore, a renewed interest in B. anthracis and SEB as bioterror threats has caused some academic, government, and industrial institutions to further investigate (or in some cases, stop investigating) the respective "biology" of this microorganism and toxin, with an immediate focus upon generating vaccines and therapeutics. Additionally, the continuing rise in antibiotic resistance among diverse clinical isolates throughout the world (e.g., vancomycin-resistant S. aureus) demands further attention now by researchers and clinicians, ultimately necessitating "novel" means of controlling bacterial pathogens and their toxins (22).SEB and other related toxins produced by S. aureus and Streptococcus pyogenes (i.e., toxic shock syndrome toxin 1 [TSST-1] plus the pyrogenic exotoxins) possess superantigenic properties that entail a marked activation of T lymphocytes with subsequent release of proinflammatory cytokines and chemokines (12-16). In large quantities, these molecules can play an important role in ill effects experienced by the host following exposure to SEB or other related protein superantigens. In vitro and in vivo studies by various groups have also shown that the adverse effects of the SEs and TSST-1 are naturally potentiated by a ubiquitous component of all gram-negative bacteria, namely, lipopolysaccharide (LPS) (4, 6, 30-32). It is this fact that suggests that an agent which blocks LPS effects might also abrogate SEB activity, as both commonly evoke elevated levels of proinflammatory cytokines and chemokines (8,(14)(15)(16).A previous study by Hoover et al. (9) reveals that B. anthracis edema factor (EF), a calcium/calmodulin-dependent adenylate cyclase that enters various eucaryotic cells via B. anthracis protective antigen (PA) (17-19), substantially decreases the p...

Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

“…6) (21). Furthermore, edema factor has a reported half-life of 2 h in the cytosol (19), which may explain edema toxin's persistent effects in the present experiments.…”

Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock

“…In in vitro or in vivo studies, ETx appeared to inhibit TNF-␣, IFN-␥, IL-12p70, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1␣, and MIP-1␤ (49,58,(61)(62)(63). However, ETx has been associated with increases in IL-6, granulocyte colony-stimulating factor, exotaxin, keratinocyte-derived chemokine (KC), IL-10, IL-1 and monocyte-selective chemokine (JE)/MCP-1 (49,58,62,63). This toxin has also been shown to inhibit activation and proliferation of CD4 ϩ T cells (49).…”

Synthesis and assembly of a full‐length human monoclonal antibody in algal chloroplasts

“…By targeting and successfully neutralizing the different components of the anthrax toxin it should be possible to reduce cell death and allow the host organism to clear the infection, thus decreasing the mortality rate of anthrax. Anti-anthrax antibodies have been used as passive immunotherapy to prevent anthrax toxicity and death in both rats and mice (Krakauer et al, 2005;Wild et al, 2003), and this same strategy could potentially work in humans.…”