Neurological and Physiological Responses of the Primate to Anthrax Toxin

Vick, J. A.; Lincoln, R. E.; Klein, F.; Mahlandt, B. G.; Walker, J. S.; Fish, D. C.

doi:10.1093/infdis/118.1.85

Cited by 30 publications

(23 citation statements)

References 2 publications

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“…However, in the present study in rats as well as in a prior study in mice, myocardial histology after LeTx challenge did not show evidence of injury that would provide a basis for direct chronotropic or inotropic effects (23). Furthermore, prior animal studies have not attributed negative inotropic or chronotropic effects to LeTx (2,6,15,35,38). Finally, patients with shock who were intensively monitored during the recent outbreak of B. anthracis were not reported to demonstrate uncharacteristic reductions in HR (3,21,22).…”

Section: Discussioncontrasting

confidence: 61%

Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats

Cui¹,

Moayeri²,

Li³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

114

172

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. Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats. Am J Physiol Regul Integr Comp Physiol 286: R699-R709, 2004. First published January 8, 2004 10.1152/ajpregu.00593.2003.-Although circulatory shock related to lethal toxin (LeTx) may play a primary role in lethality due to Bacillus anthracis infection, its mechanisms are unclear. We investigated whether LeTx-induced shock is associated with inflammatory cytokine and nitric oxide (NO) release. SpragueDawley rats with central venous and arterial catheters received 24-h infusions of LeTx (lethal factor 100 g/kg; protective antigen 200 g/kg) that produced death beginning at 9 h and a 7-day mortality rate of 53%. By 9 h, mean arterial blood pressure, heart rate, pH, and base excess were decreased and lactate and hemoglobin levels were increased in LeTx nonsurvivors compared with LeTx survivors and controls (diluent only) (P Յ 0.05 for each comparing the 3 groups). Despite these changes, arterial oxygen and circulating leukocytes and platelets were not decreased and TNF-␣, IL-1␤, IL-6, and IL-10 levels were not increased comparing either LeTx nonsurvivors or survivors to controls. Nitrate/nitrite levels and tissue histology also did not differ comparing LeTx animals and controls. In additional experiments, although 24-h infusions of LeTx and Esherichia coli LPS produced similar mortality rates (54 and 56%, respectively) and times to death (13.2 Ϯ 0.8 vs. 11.0 Ϯ 1.7 h, respectively) compared with controls, only LPS reduced circulating leukocytes, platelets, and IL-2 levels and increased TNF-␣, IL-1␣ and -1␤, IL-6, IL-10, interferon-␥, granulocyte macrophage-colony stimulating factor, RANTES, migratory inhibitory protein-1␣, -2, and -3, and monocyte chemotactic protein-1, as well as nitrate/nitrite levels (all P Յ 0.05 for the effects of LPS). Thus, in contrast to LPS, excessive inflammatory cytokine and NO release does not appear to contribute to the circulatory shock and lethality occurring with LeTx in this rat model. Although therapies to modulate these host mediators may be applicable for shock caused by LPS or other bacterial toxins, they may not with LeTx.

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Section: Discussioncontrasting

confidence: 61%

Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats

Cui¹,

Moayeri²,

Li³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

114

172

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“…The B. pertussis, E. coli (23) Brevibacterium liquifaciens (26) enzymes have been obtained in a relatively pure state. Of these three enzymes, only the last, obtained in a crystalline form (26), has a specific activity (30 ,umol min-' mg-') comparable to that calculated for EF from the data of (28,29). Most investigators consider that the pathologic changes seen in infected animals are due to the lethal toxin, composed of PA and LF.…”

Section: Resultsmentioning

confidence: 87%

Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells.

Leppla¹

1982

Proc. Natl. Acad. Sci. U.S.A.

876

658

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Anthrax toxin is composed ofthree proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). These proteins individually cause no known physiological effects in animals but in pairs produce two toxic actions. Injection of PA with LF causes death ofrats in 60 min, whereas PA with EF causes edema in the skin of rabbits and guinea pigs. The mechanisms of action of-these proteins have not beendetermined. It is shown here that EF is an adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] produced by Bacllus anthracis in an inactive form. Activation occurs upon contact with a heat-stable eukaryotic cell material. The specific activity of the resulting adenylate cyclase nearly, equals that of the most active known cyclase. In Chinese hamster ovary cells exposed to PA and EF, cAMP concentrations increase without a lag to values about 200-fold above normal, remain high in the continued presence of toxin, and decrease rapidly after its removal. The increase in cAMP is completely blocked by excess LF. It is. suggested that PA interacts with cells to form a receptor system by which EF and perhaps LF gain access to the cytoplasm.

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“…ATR ϭ anthrax toxin receptor (tumor endothelial marker-8); CMG2 ϭ capillary morphogenesis gene 2; DNI ϭ dominant-negative inhibitor; EF ϭ edema factor; Hexa-D-Arg ϭ hexa-D-arginine; LF ϭ lethal factor; MAPKK ϭ mitogen-activated protein kinase kinase; PA ϭ protective antigen; PVI ϭ polyvalent inhibitor. Adapted by permission from Reference 5. ary to central respiratory depression (27). After these early investigations, no additional studies describing this toxin's hemodynamic effects were reported over the ensuing 30 years.…”

Section: Cardiovascular Effects Of Letxmentioning

confidence: 99%

Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock

Sherer

Cui

et al. 2007

Am J Respir Crit Care Med

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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 mitogenactivated 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.

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Neurological and Physiological Responses of the Primate to Anthrax Toxin

Cited by 30 publications

References 2 publications

Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats

Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats

Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells.

Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock

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