Transcriptional stimulation of anthrax toxin receptors by anthrax edema toxin and Bacillus anthracis Sterne spore

Xu, Qing; Hesek, Eric D.; Zeng, Mingtao

doi:10.1016/j.micpath.2007.03.002

Cited by 14 publications

(14 citation statements)

References 34 publications

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“…In addition, the EF-induced rise in cyclic AMP inhibits phagocytosis, microbiocidal activity, neutrophil chemotaxis, and superoxide production, contributing to extensive physiological immune dysfunction (41). Edema toxin was also shown to contribute to increased transcription of the anthrax toxin receptor genes in host cells, theoretically contributing to enhanced receptor expression and toxin uptake (48).…”

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Kinetics of Lethal Factor and Poly-d-Glutamic Acid Antigenemia during Inhalation Anthrax in Rhesus Macaques

et al. 2009

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Systemic anthrax manifests as toxemia, rapidly disseminating septicemia, immune collapse, and death. Virulence factors include the anti-phagocytic ␥-linked poly-D-glutamic acid (PGA) capsule and two binary toxins, complexes of protective antigen (PA) with lethal factor (LF) and edema factor. We report the characterization of LF, PA, and PGA levels during the course of inhalation anthrax in five rhesus macaques. We describe bacteremia, blood differentials, and detection of the PA gene (pagA) by PCR analysis of the blood as confirmation of infection. For four of five animals tested, LF exhibited a triphasic kinetic profile. LF levels (mean ؎ standard error [SE] between animals) were low at 24 h postchallenge (0.03 ؎ 1.82 ng/ml), increased at 48 h to 39.53 ؎ 0.12 ng/ml (phase 1), declined at 72 h to 13.31 ؎ 0.24 ng/ml (phase 2), and increased at 96 h (82.78 ؎ 2.01 ng/ml) and 120 h (185.12 ؎ 5.68 ng/ml; phase 3). The fifth animal had an extended phase 2. PGA levels were triphasic; they were nondetectable at 24 h, increased at 48 h (2,037 ؎ 2 ng/ml), declined at 72 h (14 ؎ 0.2 ng/ml), and then increased at 96 h (3,401 ؎ 8 ng/ml) and 120 h (6,004 ؎ 187 ng/ml). Bacteremia was also triphasic: positive at 48 h, negative at 72 h, and positive at euthanasia. Blood neutrophils increased from preexposure (34.4% ؎ 0.13%) to 48 h (75.6% ؎ 0.08%) and declined at 72 h (62.4% ؎ 0.05%). The 72-h declines may establish a "go/no go" turning point in infection, after which systemic bacteremia ensues and the host's condition deteriorates. This study emphasizes the value of LF detection as a tool for early diagnosis of inhalation anthrax before the onset of fulminant systemic infection.

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Kinetics of Lethal Factor and Poly-d-Glutamic Acid Antigenemia during Inhalation Anthrax in Rhesus Macaques

et al. 2009

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“…Protein kinase A blockade inhibits vasopressin-mediated AQP2 membrane expression and free water uptake (30)(31)(32)(33). With respect to ET, the two anthrax toxin receptors (ANTR1 or TEM8 and ANTR2 or CMG2) that internalize PA and EF are expressed in renal tissue (34)(35)(36). Like vasopressin, EF stimulates cAMP gradients in cells starting in the perinuclear region, where A kinaseanchoring proteins participate in PKA-mediated AQP2 phosphorylation (37).…”

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confidence: 99%

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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“…High levels of cAMP generated by ET activate PKA, leading to upregulation of the ANTXR genes in monocyte-derived cells and inhibition of phospholipase A2 (sPLA-IIA) in macrophages (5,29,38,47). PKA-induced transcriptional changes are mediated through modulation of various transcription factors, including the cAMP-responsive element binding (CREB) protein, which promotes formation of transcription complexes at CRE sequences present in cAMP-responsive genes (31).…”

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Glycogen Synthase Kinase 3 Activation Is Important for Anthrax Edema Toxin-Induced Dendritic Cell Maturation and Anthrax Toxin Receptor 2 Expression in Macrophages

et al. 2011

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Anthrax edema toxin (ET) is one of two binary toxins produced by Bacillus anthracis that contributes to the virulence of this pathogen. ET is an adenylate cyclase that generates high levels of cyclic AMP (cAMP), causing alterations in multiple host cell signaling pathways. We previously demonstrated that ET increases cell surface expression of the anthrax toxin receptors (ANTXR) in monocyte-derived cells and promotes dendritic cell (DC) migration toward the lymph node-homing chemokine MIP-3␤. In this work, we sought to determine if glycogen synthase kinase 3 (GSK-3) is important for ET-induced modulation of macrophage and DC function. We demonstrate that inhibition of GSK-3 dampens ET-induced maturation and migration processes of monocytederived dendritic cells (MDDCs). Additional studies reveal that the ET-induced expression of ANTXR in macrophages was decreased when GSK-3 activity was disrupted with chemical inhibitors or with small interfering RNA (siRNA) targeting GSK-3. Further examination of the ET induction of ANTXR revealed that a dominant negative form of CREB could block the ET induction of ANTXR, suggesting that CREB or a related family member was involved in the upregulation of ANTXR. Because CREB and GSK-3 activity appeared to be important for ET-induced ANTXR expression, the impact of GSK-3 on ET-induced CREB activity was examined in RAW 264.7 cells possessing a CRE-luciferase reporter. As with ANTXR expression, the ET induction of the CRE reporter was decreased by reducing GSK-3 activity. These studies not only provide insight into host pathways targeted by ET but also shed light on interactions between GSK-3 and CREB pathways in host immune cells.

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Transcriptional stimulation of anthrax toxin receptors by anthrax edema toxin and Bacillus anthracis Sterne spore

Cited by 14 publications

References 34 publications

Kinetics of Lethal Factor and Poly-d-Glutamic Acid Antigenemia during Inhalation Anthrax in Rhesus Macaques

Kinetics of Lethal Factor and Poly-d-Glutamic Acid Antigenemia during Inhalation Anthrax in Rhesus Macaques

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

Glycogen Synthase Kinase 3 Activation Is Important for Anthrax Edema Toxin-Induced Dendritic Cell Maturation and Anthrax Toxin Receptor 2 Expression in Macrophages

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