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Infection and Immunity, January 2004, p. 430-439, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.430-439.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Anthrax Lethal Toxin Induces Human Endothelial Cell Apoptosis

James E. Kirby*

Department of Pathology, Division of Cancer Biology and Angiogenesis, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215

Received 6 May 2003/ Returned for modification 24 June 2003/ Accepted 11 September 2003

Because of its ease of dispersal and high lethality, Bacillus anthracis is one of the most feared biowarfare agents. A better understanding of anthrax pathogenesis is urgently needed to develop new therapies for systemic disease that is relatively unresponsive to antibiotics. Although experimental evidence has implicated a role for macrophages in anthrax pathogenesis, clinical and pathological observations suggest that a direct insult to the host vasculature may also be important. Two bacterial toxins, lethal toxin and edema toxin, are believed to mediate the clinical sequelae of anthrax. Here, I examined whether these toxins are directly toxic to endothelial cells, the cell type that lines the interior of blood vessels. I show for the first time that lethal toxin but not edema toxin reduces the viability of cultured human endothelial cells and induces caspase-dependent endothelial apoptosis. In addition, this toxicity affects both microvascular and large vessel endothelial cells as well as endothelial cells that have differentiated into tubules within a type I collagen extracellular matrix. Finally, lethal toxin induces cleavage of mitogen-activated protein kinase kinases in endothelial cells and inhibits phosphorylation of ERK, p38, and JNK p46. Based on the contributions of these pathways to endothelial survival, I propose that lethal toxin-mediated cytotoxicity/apoptosis results primarily through inhibition of the ERK pathway. I also hypothesize that the observed endothelial toxicity contributes to vascular pathology and hemorrhage during systemic anthrax.

* Mailing address: Department of Pathology, Division of Cancer Biology and Angiogenesis, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Yamins 309, Boston, MA 02215. Phone: (617) 667-3577. Fax: (617) 667-4533. E-mail: jekirby{at}bidmc.harvard.edu.

Editor: J. T. Barbieri

Infection and Immunity, January 2004, p. 430-439, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.430-439.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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