The Pathogenesis of the Lethal Effect of Anthrax Toxin in the Rat

“…[1][2][3] While macrophages from some strains are sensitive to the effects of anthrax lethal toxin (LeTx), 4 the exact mechanism of action for cell death remains to be solved. The host cellular machinery is known to play a key role as demonstrated by the identification of a receptor complex for LeTx [5][6][7] and downstream intracellular signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Rat survival to anthrax lethal toxin is likely controlled by a single gene

et al. 2007

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We examined whether survival of different rat strains administered anthrax lethal toxin is genetically determined. A reproducible test population of first filial generation hybrid rats was bred based on the susceptibility of progenitors to anthrax lethal toxin and to maximize genetic diversity across the strains. These rats were then tested with varying doses of anthrax lethal toxin. We found that all 'sensitive' strains died within 2 h following systemic administration of 240 mg/kg lethal toxin, while one strain survived following a five times higher dose (1.4 mg/kg). The ability of lethal toxin to lyse macrophage cultures derived from the bone marrow of these strains corresponded with in vivo results. We conclude that a rat test population can detect strain differences in response to anthrax lethal toxin. Survival is influenced by the host genome background and is likely due to a single gene with a recessive mode of inheritance.

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“…injection of anthrax toxin proteins (1)(2)(3)(4)(5)(6)(7)(8). The importance of blood vessels and endothelial cells in anthrax toxicity has been difficult to investigate because of the inability to observe progressive vascular changes without sacrificing the mammalian host.…”

mentioning

confidence: 99%

“…The combination of PA and LF is known as lethal toxin (LeTx), and the combination of PA and EF is known as edema toxin (EdTx). LeTx induces rapid death in experimental animals, and its action is associated with vascular defects and pleural effusions (4,5). Early reports indicated that EdTx did not produce significant mortality (9), but recently robust effects have been reported, including lethality in rodents (10,11).…”

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confidence: 99%

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

Bolcome

Sullivan

Zeller

et al. 2008

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

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Vascular dysfunction has been reported in human cases of anthrax, in mammalian models of Bacillus anthracis, and in animals injected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits in vivo imaging and evaluation of vasculature and cardiovascular function. Vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin action by tracking the extravasation of fluorescent microspheres in toxin-injected embryos. Lethal toxin did not induce a significant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/ vascular permeability factor (VPF) signaling pathway, and we were able to attenuate anthrax lethal toxin effects with chemical inhibitors of VEGFR function. Our study demonstrates the importance of vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.endothelial ͉ vascular permeability ͉ VEGF

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The Pathogenesis of the Lethal Effect of Anthrax Toxin in the Rat

Cited by 62 publications

References 1 publication

Pathophysiological and Biochemical Changes in Anthrax

Pathophysiological and Biochemical Changes in Anthrax

Rat survival to anthrax lethal toxin is likely controlled by a single gene

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

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