Observations on Experimental Anthrax: Demonstration of a Specific Lethal Factor produced in vivo by Bacillus anthracis

Smith, H.; Keppie, J.

doi:10.1038/173869a0

Cited by 148 publications

(107 citation statements)

References 5 publications

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“…Rapid administration of anthrax toxin or inability to serially monitor hemodynamics in prior studies or other factors may have resulted in the differences between our observations and previous ones. However, our findings are consistent with original speculation regarding the pathogenic effects of anthrax toxin (35), as well as by reports of nonsurvivors in the recent series of patients presenting with anthrax infection after exposure to contaminated mail (3,22). In these patients shock was not only a common finding early in presentation but also as disease progressed (3,22).…”

Section: Discussionsupporting

confidence: 81%

Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats

Cui¹,

Moayeri²,

Li³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

114

172

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. Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats. Am J Physiol Regul Integr Comp Physiol 286: R699-R709, 2004. First published January 8, 2004 10.1152/ajpregu.00593.2003.-Although circulatory shock related to lethal toxin (LeTx) may play a primary role in lethality due to Bacillus anthracis infection, its mechanisms are unclear. We investigated whether LeTx-induced shock is associated with inflammatory cytokine and nitric oxide (NO) release. SpragueDawley rats with central venous and arterial catheters received 24-h infusions of LeTx (lethal factor 100 g/kg; protective antigen 200 g/kg) that produced death beginning at 9 h and a 7-day mortality rate of 53%. By 9 h, mean arterial blood pressure, heart rate, pH, and base excess were decreased and lactate and hemoglobin levels were increased in LeTx nonsurvivors compared with LeTx survivors and controls (diluent only) (P Յ 0.05 for each comparing the 3 groups). Despite these changes, arterial oxygen and circulating leukocytes and platelets were not decreased and TNF-␣, IL-1␤, IL-6, and IL-10 levels were not increased comparing either LeTx nonsurvivors or survivors to controls. Nitrate/nitrite levels and tissue histology also did not differ comparing LeTx animals and controls. In additional experiments, although 24-h infusions of LeTx and Esherichia coli LPS produced similar mortality rates (54 and 56%, respectively) and times to death (13.2 Ϯ 0.8 vs. 11.0 Ϯ 1.7 h, respectively) compared with controls, only LPS reduced circulating leukocytes, platelets, and IL-2 levels and increased TNF-␣, IL-1␣ and -1␤, IL-6, IL-10, interferon-␥, granulocyte macrophage-colony stimulating factor, RANTES, migratory inhibitory protein-1␣, -2, and -3, and monocyte chemotactic protein-1, as well as nitrate/nitrite levels (all P Յ 0.05 for the effects of LPS). Thus, in contrast to LPS, excessive inflammatory cytokine and NO release does not appear to contribute to the circulatory shock and lethality occurring with LeTx in this rat model. Although therapies to modulate these host mediators may be applicable for shock caused by LPS or other bacterial toxins, they may not with LeTx.

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Section: Discussionsupporting

confidence: 81%

Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats

Cui¹,

Moayeri²,

Li³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

114

172

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“…BI-11A9 was obtained as 0.176 g of reddish orange solid in 88% yield. 1 M Tris⅐HCl, pH 8.0, for 30 min. Finally, the crystal was transferred into a cryoprotectant solution of 1.0 mM MFM3 inhibitor͞2.4 M (NH 4 ) 2 SO 4 ͞0.2 M Tris⅐HCl, pH 8.0͞2 mM EDTA͞25% glycerol and soaked at room temperature for an additional 1 min.…”

Section: Methodsmentioning

confidence: 99%

Efficient synthetic inhibitors of anthrax lethal factor

Forino

Johnson

Wong

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

125

144

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Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxican against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.

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“…Thus, live B. 34,45,47). In contrast, advantages in using strains anthracis strains that produced toxin components of inbred mice include extensively characterized were protective, whereas strains that produced genetic polymorphism, differences in resistance capsule, polysaccharide, and other somatic comlto diseases such as anthrax, and convenient size ponents, but not toxin components.…”

mentioning

confidence: 99%