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

Cui, Xizhong; Li, Yan; Li, Xuemei; Laird, Michael W.; Subramanian, Mani; Moayeri, Mahtab; Leppla, Stephen H.; Fitz, Yvonne; Su, Junwu; Sherer, Kevin; Eichacker, Peter Q.

doi:10.1086/510856

Cited by 61 publications

(92 citation statements)

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“…The effects of edema toxin in both models persisted after the toxin infusion was stopped. Of note, however, edema toxin was not associated with hemoconcentration, which might have been expected if substantial extravasation of fluid had occurred (6,30). Based on edema factor's adenyl cyclase activity, these changes appeared potentially related to direct chronotropic or systemic vasodilatory effects.…”

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confidence: 89%

“…We (6,8,30) have shown in both rat and canine models that lethal 24-h edema toxin infusions also produce rapid hypotension and tachycardia. In canines, edema toxin reduced central venous pressure and systemic vascular resistance and increased the cardiac index but did not alter the LV ejection fraction (LVEF) (30).…”

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confidence: 95%

“…This group concluded that edema toxin's recognized effect on tissue edema formation likely reduced preload and induced secondary hypotension and tachycardia. Lethal toxin, on the other hand, appeared capable of depressing myocardial function (9, 36, 37).We (6,8,30) have shown in both rat and canine models that lethal 24-h edema toxin infusions also produce rapid hypotension and tachycardia. In canines, edema toxin reduced central venous pressure and systemic vascular resistance and increased the cardiac index but did not alter the LV ejection fraction (LVEF) (30).…”

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confidence: 97%

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Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

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Okugawa

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Eichacker PQ. Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model. Am J Physiol Heart Circ Physiol 300: H1108 -H1118, 2011. First published January 7, 2011; doi:10.1152/ajpheart.01128.2010.-While anthrax edema toxin produces pronounced tachycardia and lethal toxin depresses left ventricular (LV) ejection fraction in in vivo models, whether these changes reflect direct cardiac effects as opposed to indirect ones related to preload or afterload alterations is unclear. In the present study, the effects of edema toxin and lethal toxin were investigated in a constant pressure isolated perfused rat heart model. Compared with control hearts, edema toxin at doses comparable to or less than a dose that produced an 80% lethality rate (LD 80) in vivo in rats (200, 100, and 50 ng/ml) produced rapid increases in heart rate (HR), coronary flow (CF), LV developed pressure (LVDP), dP/dt max, and rate-pressure product (RPP) that were most pronounced and persisted with the lowest dose (P Յ 0.003). Edema toxin (50 ng/ml) increased effluent and myocardial cAMP levels (P Յ 0.002). Compared with dobutamine, edema toxin produced similar myocardial changes, but these occurred more slowly and persisted longer. Increases in HR, CF, and cAMP with edema toxin were inhibited by a monoclonal antibody blocking toxin uptake and by adefovir, which inhibits the toxin's intracellular adenyl cyclase activity (P Յ 0.05). Lethal toxin at an LD 80 dose (50 ng/ml) had no significant effect on heart function but a much higher dose (500 ng/ml) reduced all parameters (P Յ 0.05). In conclusion, edema toxin produced cAMP-mediated myocardial chronotropic, inotropic, and vasodilatory effects. Vasodilation systemically with edema toxin could contribute to shock during anthrax while masking potential inotropic effects. Although lethal toxin produced myocardial depression, this only occurred at high doses, and its relevance to in vivo findings is unclear.heart function MORTALITY WITH SHOCK during the 2001 United States anthrax outbreak was high despite aggressive support (15). The risk of anthrax persists, as evidenced by recent cases of highly fatal soft tissue infections in the United Kingdom (2). Bacillus anthracis produces two toxins: lethal toxin, made up of protective antigen and lethal factor, and edema toxin, made up of protective antigen and edema factor (18, 21,28,38). Protective antigen mediates the cellular uptake of the two toxigenic components, lethal and edema factors. Lethal factor is a zinc metalloprotease that inactivates MAPK kinases (18). Edema factor has highly active calmodulin-dependent adenyl cyclase activity that acts to perturb PKA-dependent signaling (21, 25). While lethal toxin and edema toxin are associated with the development of shock during anthrax, the mechanisms underlying these effects remain unclear (28).One group (36, 37) has shown that rapid edema toxin administration in rats produces hypotension and tachycardia and reduced left...

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Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

Hicks

Okugawa

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Early reports indicated that EdTx did not produce significant mortality (9), but recently robust effects have been reported, including lethality in rodents (10,11). However, the ability to induce loss of vascular integrity and leakage has been consistently associated with LeTx (7,(10)(11)(12).…”

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Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

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Sullivan

Zeller

et al. 2008

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

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Vascular dysfunction has been reported in human cases of anthrax, in mammalian models of Bacillus anthracis, and in animals injected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits in vivo imaging and evaluation of vasculature and cardiovascular function. Vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin action by tracking the extravasation of fluorescent microspheres in toxin-injected embryos. Lethal toxin did not induce a significant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/ vascular permeability factor (VPF) signaling pathway, and we were able to attenuate anthrax lethal toxin effects with chemical inhibitors of VEGFR function. Our study demonstrates the importance of vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.endothelial ͉ vascular permeability ͉ VEGF

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“…While intoxication of the immune system allows for survival of the bacteria in the host, its effect on the cardiac tissue and vasculature are potentially necessary dissemination through the host and the final stages of infection in many animal models and human case studies [242][243][244][245]. The ability to delete the exotoxin receptor in specific tissue with the Cre/lox system in mice indicated that cardiac and smooth muscle cells are crucial for exotoxin mediated death [128].…”

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Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

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Bacillus anthracis is a Gram positive sporulating bacterium that is the causative agent of anthrax. Early steps in dissemination are understudied due to the asymptomatic and asynchronous nature of B. anthracis infections. The goals of these studies are to establish a model of the early steps of B. anthracis infections and examine how the initial site of infection and exotoxin production affect bacterial dissemination. In these studies, a mouse model was used in combination with a bioluminescent signature tagged library to determine how B.anthracis disseminates through the host and the roles of an exotoxin component, lethal factor, in colonization and dissemination. This library allowed for real time observation of dissemination and analysis of bacterial population dynamics. In the first set of experiments, mice were infected via inhalational or subcutaneous routes with the tagged library to determine how the bacterial population changed during dissemination. In inhalational and subcutaneous infections, the disseminated population was comprised of a small subset of the original library.This indicated the presence of a population bottleneck, a random decrease in genetic diversity during the infection. Surprisingly, the diminishment and location of the bottleneck varied depending on the initial site of infection. This suggested B. anthracis exploits multiple host environments and some sites may be more permissive for dissemination than others. In the second set of experiments, mice were infected with a signature tagged library where a portion of clones lacked lethal factor. Lethal factor is known to be an important virulence factor as deletion results in attenuated or complete loss of virulence in most animal models. Host survival increased when < 10% of the library produced lethal factor, but few other differences were observed. Furthermore, decreases in the proportion of lethal factor producing clones led to fewer clones disseminating. These findings suggest that a threshold of lethal factor must be ii produced for colonization and dissemination to occur in vivo. In total, this work provides an understanding of how B. anthracis is able to rapidly disseminate from a several tissues and gives insights in where future therapeutics should be focused to reduce disease incidence.iii

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

Abstract: ETx was approximately 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.

Cited by 61 publications

References 33 publications

Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

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