Anthrax

Bacillus anthracis (the bacteria that causes anthrax) produces its damage in large part through "lethal toxin." The bacteria releases this substance which can kill cells of the immune system or stimulate them to cause damage elsewhere in the body.

Research has revealed several nutrients the protect animals from this toxin.

N-acetyl-Cysteine

N-acetyl-Cysteine is an antioxidant that reduces free-radical damage inside our cells. Mice given N-acetyl-L-cysteine resisted the anthrax lethal toxin better.¹

DHEA and Melatonin

The immune cells involved with anthrax toxicity are the macrophages. These cells sample the environment within us, identify bacteria and viruses, and produce signals that can activate the immune system. Sometimes these signals are produced in abnormally high amounts, and can damage to our system. Tumor necrosis factor is one such substance, and anthrax lethal toxin can cause macrophages to release this in dangerous amounts. DHEA and melatonin, given either separately or together, moderated this toxic effect of anthrax lethal toxin.² We have information for patients at our office on dosing and use of both of these hormones. They should be used with care. The risk of adverse side-effects of these hormones, while low, is not as low as the risk of anthrax. DHEA should not be used in people under the age of 65 without laboratory testing to be sure levels are not too high.

Soy

Soy, as any plant, contains many substances that affect our physiology. Genistein is one such substance. It has beneficial effects on menopausal symptoms and blood clotting. It reduces the risk of cancer and reduces toxins in the intestine. This study in Korea showed that genistein reduced the toxicity of anthrax lethal toxin.³

¹ Hanna PC,Kruskal BA,Ezekowitz RA,Bloom BR,Collier RJ. "Role of macrophage oxidative burst in the action of anthrax lethal toxin." Molecular Medicine. 1994 Nov;1:7-18. (Issue number 1) Language- eng Research reported by Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.. =16700= = Conclusion: These results imply that the cytolytic effect of the toxin is mediated by ROIs (reactive oxygen intermediates). Additionally, cytokine production and consequent pathologies showed partial dependence on macrophage ROIs. Antioxidants moderately inhibited toxin-induced cytokine production in vitro, and BALB/c mice pretreated with N-acetyl-L-cysteine or mepacrine showed partial protection against lethal toxin. Thus ROIs are involved in both the cytolytic action of anthrax lethal toxin and the overall pathologic process in vivo. = Author's abstract: BACKGROUND: Major symptoms and death from systemic Bacillus anthracis infections are mediated by the action of the pathogen's lethal toxin on host macrophages. High levels of the toxin are cytolytic to macrophages, whereas low levels stimulate these cells to produce cytokines (interleukin-1 beta and tumor necrosis factor-alpha), which induce systemic shock and death. MATERIALS AND METHODS: Experiments were performed to assess the possibility that the oxidative burst may be involved in one or both of lethal toxin's effects on macrophages. Toximediated cell lysis, superoxide anion and cytokine production were measured. Effects of antioxidants and macrophage mutations were examined. RESULTS: RAW264.7 murine macrophages treated with high levels of toxin released large amounts of superoxide anion, beginning at about 1 hr, which correlates with the onset of cytolysis. Cytolysis cou ld be blocked with various exogenous antioxidants or with N-acetyl-L-cysteine and methionine, which promote production of the endogenous antioxidant, glutathione. Mutant murine macrophage lines deficient in production of reactive oxygen intermediates (ROIs) were relatively insensitive to the lytic effects of the toxin, whereas a line with increased oxidative burst potential showed elevated sensitivity. Also, cultured blood monocyte-derived macrophages from a patient with Chronic Granulomatous Disease, a disorder in which the phagocyte's oxidative burst is disabled, were totally resistant to toxin, in contrast to control monocytes.

² Shin S,Hur GH,Kim YB,Yeon GB,Park KJ,Park YM,Lee WS. "Dehydroepiandrosterone and melatonin prevent Bacillus anthracis lethal toxin-induced TNF production in macrophages." Cell Biology and Toxicology. 2000;16:165-74. (Issue number 3) Language- eng Research reported by CBR Department, Agency for Defense Development, Taejon, Korea. freesung@chollian.net. =16701= = Author's abstract: The lethal toxin of Bacillus anthracis, which is composed of two separate proteinaceous exotoxins, namely protective antigen and lethal factor, is central to the pathogenesis of anthrax. Low levels of this toxin are known to induce release of cytokines such as tumor necrosis factor alpha (TNF-alpha). In the present study we investigated the effect of dehydroepiandrosterone (DHEA), melatonin (MLT), or DHEA + MLT on production of lethal toxin-induced TNF-alpha in mouse peritoneal macrophages. We found that treatment with DHEA significantly inhibited the TNF-alpha production caused by anthrax lethal toxin. Exposure of MLT to anthrax lethal toxin-treated macrophages also decreased the release of TNF-alpha to the extracellular medium as compared to the control. However, combined use of DHEA and MLT also inhibited TNF-alpha release, but not more than single therapies. These results suggest that DHEA and MLT may have a therapeutic role in reducing the increased cytokine production induced by anthrax lethal toxin.

³ Shin S,Kim YB,Hur GH. "Involvement of phospholipase A2 activation in anthrax lethal toxin-induced cytotoxicity." Cell Biology and Toxicology. 1999 Feb;15:19-29. (Issue number 1) Language- eng Research reported by CBR Department, Agency for Defense Development, Yuseong, Taejon, Korea.. =16711= = Author's abstract: The molecular mechanism of cytotoxic effect exerted by the lethal toxin (LeTx) of Bacillus anthracis is not well understood. In the present study, using primary culture of mouse peritoneal macrophages, we have investigated possible cytotoxic mechanisms. LeTx was not found to induce high levels of nitric oxide (NO) production for NO-mediated toxicity. Fragmentation of DNA, a biochemical marker of apoptosis, was not observed in LeTx-treated cells. Pretreatment of cells with antioxidants such as melatonin and dehydroepiandrosterone (DHEA) did not protect the LeTx-induced cytotoxicity. (Note that a later study in Korea did find a benefit from melatonin anddehydroepiandrosterone.) However, addition of phospholipase A2 (PLA2) inhibitors (quinacrine, p-bromophenacyl bromide, manoalide, butacaine) to the culture medium resulted in the inhibition of cytotoxicity of LeTx in a dose-dependent manner. LeTx-induced cytotoxicity was also inhibited by the tyrosine-specific protein kinase inhibitor genistein, but not by the protein kinase C inhibitors staurosporine or H-7. The results of these studies indicate a role for PLA2 and protein kinase in the cytotoxic mechanism of macrophages by anthrax lethal toxin.

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