<i>B. anthracis</i>edema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model

Li, Yan; Cui, Xizhong; Solomon, Steven B.; Remy, Kenneth E.; Fitz, Yvonne; Eichacker, Peter Q.

doi:10.1152/ajpheart.00185.2013

Cited by 23 publications

(32 citation statements)

References 44 publications

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“…Small molecule inhibitors of LF are also under active development [92]. Adefovir dipivoxyl, an ATP analogue used for hepatitis B treatment in humans, was found to be an effective inhibitor of EF in vitro and in some in vivo models [72, 93, 94]. One obvious advantage of these small molecule inhibitors of LF and EF is that they should be effective against the toxins that have already gained entry into the cytosol of target cells.…”

Section: Anthrax Treatment and Preventionmentioning

confidence: 99%

Anthrax lethal and edema toxins in anthrax pathogenesis

Liu¹,

Moayeri²,

Leppla³

2014

Trends in Microbiology

186

189

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The pathophysiological effects resulting from many bacterial diseases are caused by exotoxins released by the bacteria. Bacillus anthracis, a spore-forming bacterium, is such a pathogen, causing anthrax through a combination of bacterial infection and toxemia. B. anthracis causes natural infection in humans and animals and has been a top bioterrorism concern since the 2001 anthrax attacks in the USA. The exotoxins secreted by B. anthracis use CMG2 as the major toxin receptor and play essential roles in pathogenesis during the entire course of the disease. This review focuses on the activities of anthrax toxins and their roles in initial and late stages of anthrax infection.

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Section: Anthrax Treatment and Preventionmentioning

confidence: 99%

Anthrax lethal and edema toxins in anthrax pathogenesis

Liu¹,

Moayeri²,

Leppla³

2014

Trends in Microbiology

186

189

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“…Optional antimicrobials include the following: ciprofloxacin, levofloxacin, moxifloxacin, doxycycline, amoxicillin, clindamycin, meropenem, penicillin or ampicillin, linezolid, chloramphenicol, rifampin, and vancomycin. It should be mentioned that only in vitro sensitivity data are available for the majority of the suggested antimicrobial drugs (21), while there is a substantial gap in knowledge regarding their individual in vivo efficacy, as well as the efficacy of combined therapy.…”

mentioning

confidence: 99%

Efficacy of Single and Combined Antibiotic Treatments of Anthrax in Rabbits

Weiss

Altboum

Glinert

et al. 2015

Antimicrob Agents Chemother

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Respiratory anthrax is a fatal disease in the absence of early treatment with antibiotics. Rabbits are highly susceptible to infection with Bacillus anthracis spores by intranasal instillation, succumbing within 2 to 4 days postinfection. This study aims to test the efficiency of antibiotic therapy to treat systemic anthrax in this relevant animal model. Delaying the initiation of antibiotic administration to more than 24 h postinfection resulted in animals with systemic anthrax in various degrees of bacteremia and toxemia. As the onset of symptoms in humans was reported to start on days 1 to 7 postexposure, delaying the initiation of treatment by 24 to 48 h (time frame for mass distribution of antibiotics) may result in sick populations. We evaluated the efficacy of antibiotic administration as a function of bacteremia levels at the time of treatment initiation. Here we compare the efficacy of treatment with clarithromycin, amoxicillin-clavulanic acid (Augmentin), imipenem, vancomycin, rifampin, and linezolid to the previously reported efficacy of doxycycline and ciprofloxacin. We demonstrate that treatment with amoxicillin-clavulanic acid, imipenem, vancomycin, and linezolid were as effective as doxycycline and ciprofloxacin, curing rabbits exhibiting bacteremia levels of up to 10 5 CFU/ml. Clarithromycin and rifampin were shown to be effective only as a postexposure prophylactic treatment but failed to treat the systemic (bacteremic) phase of anthrax. Furthermore, we evaluate the contribution of combined treatment of clindamycin and ciprofloxacin, which demonstrated improvement in efficacy compared to ciprofloxacin alone.

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“…However, it did not alter the GFR in kidneys under constant pressure. Thus, the effects of ET on water and sodium reabsorption, urine osmolality, and urine flow did not appear to be related to the toxin's vascular effects (48).…”

Section: Discussionmentioning

confidence: 87%

Bacillus anthracis Edema Toxin Increases Fractional Free Water and Sodium Reabsorption in an Isolated Perfused Rat Kidney Model

et al. 2017

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Bacillus anthracis edema toxin (ET) consists of protective antigen (PA), necessary for host cell toxin uptake, and edema factor (EF), the toxic moiety which increases host cell cyclic AMP (cAMP). Since vasopressin stimulates renal water and sodium reabsorption via increased tubular cell cAMP levels, we hypothesized the ET would also do so. To test this hypothesis, we employed an isolated perfused rat kidney model. Kidneys were isolated and perfused with modified Krebs-Henseleit buffer. Perfusate and urine samples were obtained at baseline and every 10 min over 150 min following the addition of challenges with or without treatments to the perfusate. In kidneys perfused under constant flow or constant pressure, compared to PA challenge (n ϭ 14 or 15 kidneys, respectively), ET (13 or 15 kidneys, respectively) progressively increased urine cAMP levels, water and sodium reabsorption, and urine osmolality and decreased urine output (P Յ 0.04, except for sodium reabsorption under constant pressure [P ϭ 0.17]). In ET-challenged kidneys, compared to placebo treatment, adefovir, an EF inhibitor, decreased urine cAMP levels, water and sodium reabsorption, and urine osmolality and increased urine output, while raxibacumab, a PA-directed monoclonal antibody (MAb), decreased urine cAMP levels, free water reabsorption, and urine osmolality and increased urine output (P Յ 0.03 except for urine output with raxibacumab [P ϭ 0.17]). Upon immunohistochemistry, aquaporin 2 was concentrated along the apical membrane of tubular cells with ET but not PA, and urine aquaporin 2 levels were higher with ET (5.52 Ϯ 1.06 ng/ml versus 1.51 Ϯ 0.44 ng/ml [means Ϯ standard errors of the means {SEM}; P ϭ 0.0001). Edema toxin has renal effects that could contribute to extravascular fluid collection characterizing anthrax infection clinically.KEYWORDS anthrax, edema toxin, kidney, water reabsorption B acillus anthracis infection is characterized clinically by the marked retention and extravasation of fluid, which can compromise cardiopulmonary function and impair host defense and tissue repair (1-6). Although the loss of vascular integrity and lymphatic obstruction contribute to this fluid accumulation, the significant hyponatremia in patients in the 2001 U.S. inhalational and 2009 UK soft tissue outbreaks suggests that alterations in renal water and sodium handling may also contribute (3, 5, 7). Notably, of the two toxins produced by B. anthracis, edema toxin (ET) but not lethal toxin (LT) infusion reduced serum sodium levels in canines (8). While ET is known to produce localized edema when injected subcutaneously, understanding whether it alters renal water and sodium handling has important therapeutic implications for the fluid management of patients with severe B. anthracis infection.Edema toxin consists of protective antigen (PA), the component necessary for host cell uptake of edema factor (EF), the toxic moiety (9, 10). Edema factor has calmodulin-

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B. anthracisedema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model

Cited by 23 publications

References 44 publications

Anthrax lethal and edema toxins in anthrax pathogenesis

Anthrax lethal and edema toxins in anthrax pathogenesis

Efficacy of Single and Combined Antibiotic Treatments of Anthrax in Rabbits

Bacillus anthracis Edema Toxin Increases Fractional Free Water and Sodium Reabsorption in an Isolated Perfused Rat Kidney Model

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