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15 February 2007

Volume 195, Number 4
The Journal of Infectious Diseases 2007;195:572–580
This article is in the public domain, and no copyright is claimed.
0022-1899/2007/19504-0015$15.00
DOI: 10.1086/510856
MAJOR ARTICLE

Bacillus anthracis Edema and Lethal Toxin Have Different Hemodynamic Effects but Function Together to Worsen Shock and Outcome in a Rat Model

Xizhong Cui,1

Yan Li,1

Xuemei Li,1

Michael W. Laird,3

Mani Subramanian,3

Mahtab Moayeri,2

Stephen H. Leppla,2

Yvonne Fitz,1

Junwu Su,1

Kevin Sherer,1 and

Peter Q. Eichacker1

1Critical Care Medicine Department, Clinical Center, and 2National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, and 3Human Genome Sciences, Rockville, Maryland

Introduction.To better define the contribution of edema toxins (ETx) and lethal toxins (LeTx) to shock with Bacillus anthracis, recombinant preparations of each were investigated alone or together in rats.

Methods and results.Lethal dose ranges (0%–100% lethality) of ETx (200–800 μg/kg as a 24‐h infusion) were higher than those of LeTx (12.5–200 μg/kg) ( ). However, compared with LeTx, similarly lethal ETx doses produced earlier and greater reductions in mean blood pressure (MBP) and increased, rather than decreased, heart rate (HR) ( for all). Combining either similar weight or lethal doses of ETx and LeTx increased the hazard ratio for death (log ± standard error) similar to the sum calculated with the toxin’s effects alone ( observed vs. calculated for similar weight and vs. for similar lethal doses; for both). Early (10 h) and late during infusion, ETx and LeTx together also altered MBP and HR in patterns consistent with the sum of their individual effects.

Conclusions.ETx was 10 times less lethal than LeTx but produced greater hypotension and added to the latter’s harmful effects. These findings suggest that it may be appropriate for antitoxin therapies for B. anthracis to target both ETx and LeTx.

Received 22 June 2006; accepted 22 August 2006; electronically published 3 January 2007.

  • (See the editorial commentary by Artenstein, on pages 471–3.)

Reprints or correspondence: Dr. Peter Q. Eichacker, Critical Care Medicine Dept., National Institutes of Health, Bldg. 10, Rm. 2C145, Bethesda, MD 20892 ().

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Christian A. Schmittinger, Martin W. Dünser, Ganbat Tsenddorj. (2009) Norepinephrine in anthrax-associated shock: Even worse than figs?*. Critical Care Medicine 37:4, 1510-1513
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Te-Hui Liu, Jon Oscherwitz, Bruce Schnepp, Jana Jacobs, Fen Yu, Kemp B Cease, Philip R Johnson. (2009) Genetic Vaccines for Anthrax Based on Recombinant Adeno-associated Virus Vectors. Molecular Therapy 17:2, 373-379
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Ping-Jen (Joe) Chou, Catherine A. Newton, Izabella Perkins, Herman Friedman, Thomas W. Klein. (2009) Suppression of Dendritic Cell Activation by Anthrax Lethal Toxin and Edema Toxin Depends on Multiple Factors Including Cell Source, Stimulus Used, and Function Tested. DNA and Cell Biology 27:12, 637-648
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Yan Li, Xizhong Cui, Xuemei Li, Steven B. Solomon, Robert L. Danner, Steven M. Banks, Yvonne Fitz, Djillali Annane, Charles Natanson, Peter Q. Eichacker. (2008) Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model. Intensive Care Medicine 34:3, 568-577
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R. E. Bolcome, S. E. Sullivan, R. Zeller, A. P. Barker, R. J. Collier, J. Chan. (2008) Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature. Proceedings of the National Academy of Sciences 105:7, 2439-2444
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Dimitrios G Bouzianas. (2007) Potential biological targets of Bacillus anthracis in anti-infective approaches against the threat of bioterrorism. Expert Review of Anti-infective Therapy 5:4, 665-684
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Yan Li, Kevin Sherer, Xizhong Cui, Peter Q Eichacker. (2007) New insights into the pathogenesis and treatment of anthrax toxin-induced shock. Expert Opinion on Biological Therapy 7:6, 843-854
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Jose Garnacho-Montero, Carlos Ortiz-Leyba. (2007) Optimizing the treatment of a new horseman of the Apocalypse*. Critical Care Medicine 35:6, 1626-1627
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Andrew W. Artenstein. (2007) Anthrax: From Antiquity to Answers. The Journal of Infectious Diseases 195:4, 471-473
Online publication date: 15-Feb-2007.
Citation-Full Text-PDF Version (148 kB)

  • Potential conflicts of interest: M.S. owns stock options and is an employee of Human Genome Sciences. M.W.L. owns stock in and is a former employee of Human Genome Sciences. All other authors report no conflicts.

    Presented in part: American Thoracic Society meeting, San Diego, 19–24 May 2006 (abstract A803, poster 107).

    Financial support: Trans–National Institutes of Health/Food and Drug Administration (biodefense program grant).

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