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

Bacillus anthracis Edema and Lethal Toxin Have Different Hemodynamic Effects but Function Together to Worsen Shock and Outcome in a Rat Model.
J Infect Dis. 2007 Feb 15;195(4):572-80. Epub 2007 Jan 3.

Cui X,
Li Y,
Li X,
Laird MW,
Subramanian M,
Moayeri M,
Leppla SH,
Fitz Y,
Su J,
Sherer K,
Eichacker PQ.
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA. peichacker@mail.cc.nih.gov.

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 mu g/kg as a 24-h infusion) were higher than those of LeTx (12.5-200 mu g/kg) (P<.0001). 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) (P<.05 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 (2.6+/-1.1 observed vs. 2.9+/-1.0 calculated for similar weight and 3.1+/-1.0 vs. 3.9+/-1.5 for similar lethal doses; P=.5 for both). Early
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.

University of Chicago Press

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Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock: Implications for Therapy.

Am J Respir Crit Care Med. 2007 Feb 1;175(3):211-21.

Sherer K,
Li Y,
Cui X,
Eichacker PQ.
Critical Care Medicine Department, National Institutes of Health, Building 10, Room 2C145, Bethesda, MD 20892. peichacker@cc.nih.gov.

Recent research regarding the structure and function of Bacillus anthracis lethal (LeTx) and edema (ETx) toxins provides growing insights into the pathophysiology and treatment of shock with this lethal bacteria. These are both binary-type toxins composed of protective antigen necessary for their cellular uptake and either lethal or edema factors, the toxigenic moieties.

The primary cellular receptors for protective antigen have been identified and constructed and key steps in the extracellular processing and internalization of the toxins clarified. Consistent with the lethal factor's primary action as an intracellular endopeptidase targeting mitogen-activated protein kinase kinases, growing evidence indicates that shock with this toxin does not result from an excessive inflammatory response.

In fact, the potent immunosuppressive effects of LeTx may actually contribute to the establishment and persistence of infection. Instead, shock with LeTx may be related to the direct injurious effects of lethal factor on endothelial cell function. Despite the importance of LeTx, very recent studies show that edema factor, a potent adenyl cyclase, has the ability to make a substantial contribution to shock caused by B. anthracis and works additively with LeTx.

Furthermore, ETx may contribute to the immunosuppressive effects of LeTx. Therapies under development that target several different steps in the cellular uptake and function of these two toxins have been effective in in vitro and in vivo systems. Understanding how best to apply these agents clinically and how they interact with conventional treatments should be goals for future research.

Key Words: anthrax • toxin • shock • treatment

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