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Infection and Immunity, April 2007, p. 1895-1903, Vol. 75, No. 4
0019-9567/07/$08.00+0     doi:10.1128/IAI.01632-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Contributions of Histamine, Prostanoids, and Neurokinins to Edema Elicited by Edema Toxin from Bacillus anthracis{triangledown}

Jeffrey Tessier,1* Candace Green,1 Diana Padgett,2 Wei Zhao,3 Lawrence Schwartz,4 Molly Hughes,1 and Erik Hewlett1

Division of Infectious Diseases and International Health,1 Department of Pathology, University of Virginia, Charlottesville, Virginia,2 Divisions of Rheumatology, Allergy, and Immunology in the Departments of Pediatrics,3 Internal Medicine, Virginia Commonwealth University, Richmond, Virginia4

Received 10 October 2006/ Returned for modification 13 November 2006/ Accepted 17 January 2007

Bacillus anthracis edema toxin (ET), composed of protective antigen and an adenylate cyclase edema factor (EF), elicits edema in host tissues, but the target cells and events leading from EF-mediated cyclic-AMP production to edema are unknown. We evaluated the direct effect of ET on several cell types in vitro and tested the possibility that mediators of vascular leakage, such as histamine, contribute to edema in rabbits given intradermal ET. ET increased the transendothelial electrical resistance of endothelial monolayers, a response that is mechanistically inconsistent with the in vivo vascular leakage induced by ET. Screening of several drugs by intradermal treatment prior to toxin injection demonstrated reduced ET-induced vascular leakage with a cyclo-oxygenase inhibitor (indomethacin), agents that interfere with histamine (pyrilamine or cromolyn), or a neurokinin antagonist (spantide). Systemic administration of indomethacin or celecoxib (cyclo-oxygenase inhibitors), pyrilamine, aprepitant (a neurokinin 1 receptor antagonist), or indomethacin with pyrilamine significantly reduced vascular leakage associated with ET. Although the effects of pyrilamine, cromolyn, or aprepitant on ET-induced vascular leakage suggest a possible role for mast cells (MC) and sensory neurons in ET-induced edema, ET did not elicit degranulation of human skin MC or substance P release from NT2N cells in vitro. Our results indicate that ET, acting indirectly or directly on a target yet to be identified, stimulates the production/release of multiple inflammatory mediators, specifically neurokinins, prostanoids, and histamine. These mediators, individually and through complex interactions, increase vascular permeability, and interventions directed at these mediators may benefit hosts infected with B. anthracis.

* Corresponding author. Mailing address: University of Virginia Health Sciences Center, Box 800419, Charlottesville, VA 22908. Phone: (434) 924-5267. Fax: (434) 982-3830. E-mail: jmt6e{at}virginia.edu.

{triangledown} Published ahead of print on 29 January 2007.

Editor: D. L. Burns

Infection and Immunity, April 2007, p. 1895-1903, Vol. 75, No. 4
0019-9567/07/$08.00+0     doi:10.1128/IAI.01632-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Larabee, J. L., DeGiusti, K., Regens, J. L., Ballard, J. D. (2008). Bacillus anthracis Edema Toxin Activates Nuclear Glycogen Synthase Kinase 3{beta}. Infect. Immun. 76: 4895-4904 [Abstract] [Full Text]  


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