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Infect. Immun. doi:10.1128/IAI.01632-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mediators of Edema Elicited by Edema Toxin from Bacillus anthracis: contributions from histamine, prostanoids, and neurokinins

Division of Infectious Diseases and International Health; and Department of Pathology, University of Virginia, Charlottesville, Virginia, USA. Divisions of Rheumatology, Allergy, and Immunology in the Departments of Pediatrics; and Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

^* To whom correspondence should be addressed. Email: jmt6e{at}virginia.edu.

	Abstract

Bacillus anthracis edema toxin (ET), composed of protective antigen (PA) 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 intra-dermal ET. ET increased 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 intra-dermal treatment prior to toxin injection demonstrated reduced ET 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, (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 vascular leakage suggest a possible role for mast cells (MC) and sensory neurons in ET 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 yet to be identified target, 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.