Special Issue "Anthrax Toxin"
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A special issue of Toxins (ISSN 2072-6651).
Deadline for manuscript submissions: closed (30 April 2012)
Special Issue Editor
Guest Editor
Prof. Dr. Jean-Nicolas Tournier
Department of Microbiology, Unité Interactions Hôtes-agents Pathogènes, Institut de Recherche Biomédicale des Armées, BP 87, 24 avenue des maquis du Grésivaudan, 38702 La Tronche, France
E-Mail: jntournier@crssa.net
Interests: microbial toxins in host pathogen interactions; cell cytoskeleton; toxins and immune system; MAP kinases; adeylate cyclase; toxins and cell signaling; anthrax toxins
Special Issue Information
Dear Colleagues,
Bacillus anthracis three component toxins have been discovered 65 years ago, but their role in anthrax pathogenesis has been slowly unveiled. Anthrax toxins are formed by the association of three nontoxic factors. These three factors are the protective antigen (PA), which is the ‘binding’ factor orchestrating the entry into the cell, and the lethal factor (LF) and edema factor (EF) which bear respectively a toxic activity (metalloprotease and adenylate cyclase). Intravenous injections of PA + LF (lethal toxin, LT) have been shown to be lethal in several animal models, while intradermal injections of PA + EF (edema toxin, ET) induce edema in the subcutaneous tissues. Crystal structures have been obtained for all three components. Two cell receptors have been proposed and their ubiquitous expression explains the diverse effects of toxins on vertebrate cells. The biochemical and cellular mechanisms of entry have been described, although numerous questions still remain. The list of intracellular toxin targets is constantly growing, suggesting that we only see the tip of the iceberg. At a larger scale, the toxin effects vary from innate and adaptive immune system impairment to vascular shock, largely participating in the virulence. The large corpus of knowledge on anthrax toxins gathered over the last decades has allowed developing medical countermeasures such as chemical inhibitors and monoclonal antibodies. Moreover, the PA forms still the pillar of all anthrax vaccines emphasising the scientific interest of anthrax toxins.
This special issue of ‘Toxins’ intends to cover all aspects of anthrax toxin biology from the basic science up to the medical applications. It is expected to reflect as accurately as possible the vivid aspects of the field.
Dr. Jean-Nicolas Tournier
Guest Editor
Submission
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Keywords
- anthrax toxins
- protective antigen
- lethal factor
- edema factor
- metalloprotease
- adenylyl cyclase
Published Papers (19 papers)
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Received: 19 May 2011; in revised form: 2 June 2011 / Accepted: 7 June 2011 / Published: 14 June 2011
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Abstract: The pathological actions of anthrax toxin require the activities of its edema factor (EF) and lethal factor (LF) enzyme components, which gain intracellular access via its receptor-binding component, protective antigen (PA). LF is a metalloproteinase with specificity for selected mitogen-activated protein kinase kinases (MKKs), but its activity is not directly lethal to many types of primary and transformed cells in vitro. Nevertheless, in vivo treatment of several animal species with the combination of LF and PA (termed lethal toxin or LT) leads to morbidity and mortality, suggesting that LT-dependent toxicity is mediated by cellular interactions between host cells. Decades of research have revealed that a central hallmark of this toxicity is the disruption of key cellular barriers required to maintain homeostasis. This review will focus on the current understanding of the effects of LT on barrier function, highlighting recent progress in establishing the molecular mechanisms underlying these effects.
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Received: 3 May 2011; in revised form: 3 June 2011 / Accepted: 7 June 2011 / Published: 20 June 2011
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Abstract: Bacillus anthracis, similar to other bacterial pathogens, has evolved effective immune evasion strategies to prolong its survival in the host, thus ensuring the unchecked spread of the infection. This function is subserved by lethal (LT) and edema (ET) toxins, two exotoxins produced by vegetative anthrax bacilli following germination of the spores. The structure of these toxins and the mechanism of cell intoxication are topics covered by other reviews in this issue. Here we shall discuss how B. anthracis uses LT and ET to suppress the immune defenses of the host, focusing on T lymphocytes, the key players in adaptive immunity. We shall also summarize recent findings showing that, depending on its concentration, ET has the ability not only to suppress T cell activation but also to promote the polarization of CD4+ T cells to the Th2 and Th17 subsets, highlighting the potential use of this toxin as an immunomodulator.
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Received: 30 April 2011; in revised form: 11 June 2011 / Accepted: 21 June 2011 / Published: 23 June 2011
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Abstract: Anthrax lethal toxin (LeTx) and edema toxin (EdTx) have been shown to alter hemodynamics in the rodent model, while LeTx primarily is reported to induce extensive tissue pathology. However, the rodent model has limitations when used for comparison to higher organisms such as humans. The rabbit model, on the other hand, has gained recognition as a useful model for studying anthrax infection and its pathophysiological effects. In this study, we assessed the hemodynamic effects of lethal toxin (LeTx) and edema toxin (EdTx) in the rabbit model using physiologically relevant amounts of the toxins. Moreover, we further examine the pathological effects of LeTx on cardiac tissue. We intravenously injected Dutch-belted rabbits with either low-dose and high-dose recombinant LeTx or a single dose of EdTx. The animals’ heart rate and mean arterial pressure were continuously monitored via telemetry until either 48 or 72 h post-challenge. Additional animals challenged with LeTx were used for cardiac troponin I (cTnI) quantitation, cardiac histopathology, and echocardiography. LeTx depressed heart rate at the lower dose and mean arterial pressure (MAP) at the higher dose. EdTx, on the other hand, temporarily intensified heart rate while lowering MAP. Both doses of LeTx caused cardiac pathology with the higher dose having a more profound effect. Lastly, left-ventricular dilation due to LeTx was not apparent at the given time-points. Our study demonstrates the hemodynamic effects of anthrax toxins, as well as the pathological effects of LeTx on the heart in the rabbit model, and it provides further evidence for the toxins’ direct impact on the heart.
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Received: 29 April 2011; in revised form: 7 July 2011 / Accepted: 4 August 2011 / Published: 9 August 2011
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Abstract: The primary immunogenic component of the currently approved anthrax vaccine is the protective antigen (PA) unit of the binary toxin system. PA-specific antibodies neutralize anthrax toxins and protect against infection. Recent research has determined that in humans, only antibodies specific for particular determinants are capable of effecting toxin neutralization, and that the neutralizing epitopes recognized by these antibodies are distributed throughout the PA monomer. The mechanisms by which the majority of these epitopes effect neutralization remain unknown. In this report we investigate the process by which a human monoclonal antibody specific for the amino-terminal domain of PA neutralizes lethal toxin in an in vitro assay of cytotoxicity, and find that it neutralizes LT by blocking the requisite cleavage of the amino-terminal 20 kD portion of the molecule (PA20) from the remainder of the PA monomer. We also demonstrate that the epitope recognized by this human monoclonal does not encompass the 166RKKR169 furin recognition sequence in domain 1 of PA.
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Received: 10 June 2011; in revised form: 6 August 2011 / Accepted: 10 August 2011 / Published: 15 August 2011
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Abstract: Anthrax is a highly lethal infectious disease caused by the spore-forming bacterium Bacillus anthracis. It not only causes natural infection in humans but also poses a great threat as an emerging bioterror agent. The lethality of anthrax is primarily attributed to the two major virulence factors: toxins and capsule. An extensive effort has been made to generate therapeutically useful monoclonal antibodies to each of the virulence components: protective antigen (PA), lethal factor (LF) and edema factor (EF), and the capsule of B. anthracis. This review summarizes the current status of anti-anthrax mAb development and argues for the potential therapeutic advantage of a cocktail of mAbs that recognize different epitopes or different virulence factors.
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Received: 2 June 2011; in revised form: 24 August 2011 / Accepted: 6 September 2011 / Published: 7 September 2011
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Abstract: A major virulence factor of Bacillus anthracis is the anthrax Lethal Toxin (LeTx), a bipartite toxin composed of Protective Antigen and Lethal Factor. Systemic administration of LeTx to laboratory animals leads to death associated with vascular leakage and pulmonary edema. In this study, we investigated whether systemic exposure of mice to LeTx would induce gene expression changes associated with vascular/capillary leakage in lung tissue. We observed enhanced susceptibility of A/J mice to death by systemic LeTx administration compared to the C57BL/6 strain. LeTx-induced groups of both up- and down-regulated genes were observed in mouse lungs 6 h after systemic administration of wild type toxin compared to lungs of mice exposed to an inactive mutant form of the toxin. Lungs of the less susceptible C57BL/6 strain showed 80% fewer differentially expressed genes compared to lungs of the more sensitive A/J strain. Expression of genes known to regulate vascular permeability was modulated by LeTx in the lungs of the more susceptible A/J strain. Unexpectedly, the largest set of genes with altered expression was immune specific, characterized by the up-regulation of lymphoid genes and the down-regulation of myeloid genes. Transcripts encoding neutrophil chemoattractants, modulators of tumor regulation and angiogenesis were also differentially expressed in both mouse strains. These studies provide new directions for the investigation of vascular leakage and pulmonary edema induced by anthrax LeTx.
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Received: 24 August 2011; in revised form: 8 September 2011 / Accepted: 9 September 2011 / Published: 20 September 2011
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Abstract: Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 outbreaks and the newly identified injectional drug use form of disease in the UK and Germany have been associated with relatively high mortality rates. One notable aspect of these cases has been the difficulty in supporting patients once shock has developed. Anthrax bacilli produce several different components which likely contribute to this shock. Growing evidence indicates that both major anthrax toxins may produce substantial cardiovascular dysfunction. Lethal toxin (LT) can alter peripheral vascular function; it also has direct myocardial depressant effects. Edema toxin (ET) may have even more pronounced peripheral vascular effects than LT, including the ability to interfere with the actions of conventional vasopressors. Additionally, ET also appears capable of interfering with renal sodium and water retention. Importantly, the two toxins exert their actions via quite different mechanisms and therefore have the potential to worsen shock and outcome in an additive fashion. Finally, both toxins have the ability to inhibit host defense and microbial clearance, possibly contributing to the very high bacterial loads noted in patients dying with anthrax. This last point is clinically relevant since emerging data has begun to implicate other bacterial components such as anthrax cell wall in the shock and organ injury observed with infection. Taken together, accumulating evidence regarding the potential contribution of LT and ET to anthrax-associated shock supports efforts to develop adjunctive therapies that target both toxins in patients with progressive shock.
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Received: 8 July 2011; in revised form: 1 October 2011 / Accepted: 9 October 2011 / Published: 20 October 2011
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Abstract: Systemic anthrax disease is characterized by vascular leakage pathologies. We previously reported that anthrax lethal toxin (LT) induces human endothelial barrier dysfunction in a cell death-independent manner with actin stress fiber formation and disruption of adherens junctions (AJs). In the present study, we further characterize the molecular changes in the AJ complex and investigate whether AJ structure and barrier function can be preserved by modulating key cytoskeletal signaling pathways. Here, we show that LT reduces total VE-cadherin protein and gene expression but the expression of the key linker protein beta-catenin remained unchanged. The changes in VE-cadherin expression correlated temporally with the appearance of actin stress fibers and a two-fold increase in phosphorylation of the stress fiber-associated protein myosin light chain (p-MLC) and cleavage of Rho-associated kinase-1 (ROCK-1). Co-treatment with ROCK inhibitors (H-1152 and Y27632), but not an inhibitor of MLC kinase (ML-7), blocked LT-induced p-MLC enhancement and stress fiber formation. This was accompanied by the restoration of VE-cadherin expression and membrane localization, and attenuation of the LT-induced increase in monolayer permeability to albumin. Together, these findings suggest the ROCK pathway may be a relevant target for countering LT-mediated endothelial barrier dysfunction.
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Received: 1 September 2011; in revised form: 3 November 2011 / Accepted: 7 November 2011 / Published: 16 November 2011
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Abstract: B. anthracis is a bioweapon of primary importance and its pathogenicity depends on its lethal and edema toxins, which belong to the A-B model of bacterial toxins, and on its capsule. These toxins are secreted early in the course of the anthrax disease and for this reason antibiotics must be administered early, in addition to other limitations. Antibodies (Abs) may however neutralize those toxins and target this capsule to improve anthrax treatment, and many Abs have been developed in that perspective. These Abs act at various steps of the cell intoxication and their mechanisms of action are detailed in the present review, presented in correlation with structural and functional data. The potential for clinical application is discussed for Abs targeting each step of entry, with four of these molecules already advancing to clinical trials. Paradoxically, certain Abs may also enhance the lethal toxin activity and this aspect will also be presented. The unique paradigm of Abs neutralizing anthrax toxins thus exemplifies how they may act to neutralize A-B toxins and, more generally, be active against infectious diseases.
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Received: 9 December 2011; in revised form: 23 December 2011 / Accepted: 17 January 2012 / Published: 19 January 2012
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Abstract: Lethal toxin (LT) of Bacillus anthracis reduces the production of a number of inflammatory mediators, including transcription factors, chemokines and cytokines in various human cell lines, leading to down-regulation of the host inflammatory response. Previously we showed that the reduction of interleukin-8 (IL-8) is a sensitive marker of LT-mediated intoxication in human neutrophil-like NB-4 cells and that IL-8 levels are restored to normality when therapeutic monoclonal antibodies (mAb) with toxin-neutralising (TN) activity are added. We used this information to develop cell-based assays that examine the effects of TN therapeutic mAbs designed to treat LT intoxication and here we extend these findings. We present an in vitro assay based on human endothelial cell line HUVEC jr2, which measures the TN activity of therapeutic anti-LT mAbs using IL-8 as a marker for intoxication. HUVEC jr2 cells have the advantage over NB-4 cells that they are adherent, do not require a differentiation step and can be used in a microtitre plate format and therefore can facilitate high throughput analysis. This human cell-based assay provides a valid alternative to the mouse macrophage assay as it is a more biologically relevant model of the effects of toxin-neutralising antibodies in human infection.
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Received: 10 January 2012; in revised form: 21 January 2012 / Accepted: 26 January 2012 / Published: 6 February 2012
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Abstract: Bacillus anthracis, the agent of anthrax, has gained virulence through its exotoxins produced by vegetative bacilli and is composed of three components forming lethal toxin (LT) and edema toxin (ET). So far, little is known about the effects of these toxins on the eukaryotic cytoskeleton. Here, we provide an overview on the general effects of toxin upon the cytoskeleton architecture. Thus, we shall discuss how anthrax toxins interact with their receptors and may disrupt the interface between extracellular matrix and the cytoskeleton. We then analyze what toxin molecular effects on cytoskeleton have been described, before discussing how the cytoskeleton may help the pathogen to corrupt general cell processes such as phagocytosis or vascular integrity.
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Received: 23 April 2012; in revised form: 15 June 2012 / Accepted: 27 June 2012 / Published: 6 July 2012
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Abstract: Since the isolation of Bacillus anthracis exotoxins in the 1960s, the detrimental activity of edema factor (EF) was considered as adenylyl cyclase activity only. Yet the catalytic site of EF was recently shown to accomplish cyclization of cytidine 5′-triphosphate, uridine 5′-triphosphate and inosine 5′-triphosphate, in addition to adenosine 5′-triphosphate. This review discusses the broad EF substrate specificity and possible implications of intracellular accumulation of cyclic cytidine 3′:5′-monophosphate, cyclic uridine 3′:5′-monophosphate and cyclic inosine 3′:5′-monophosphate on cellular functions vital for host defense. In particular, cAMP-independent mechanisms of action of EF on host cell signaling via protein kinase A, protein kinase G, phosphodiesterases and CNG channels are discussed.
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Received: 5 June 2012; in revised form: 21 June 2012 / Accepted: 2 July 2012 / Published: 10 July 2012
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Abstract: The mechanism of phagosome escape by intracellular pathogens is an important step in the infectious cycle. During the establishment of anthrax, Bacillus anthracis undergoes a transient intracellular phase in which spores are engulfed by local phagocytes. Spores germinate inside phagosomes and grow to vegetative bacilli, which emerge from their resident intracellular compartments, replicate and eventually exit from the plasma membrane. During germination, B. anthracis secretes multiple factors that can help its resistance to the phagocytes. Here the possible role of B. anthracis toxins, phospholipases, antioxidant enzymes and capsules in the phagosomal escape and survival, is analyzed and compared with that of factors of other microbial pathogens involved in the same type of process.
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Received: 19 June 2012; in revised form: 4 July 2012 / Accepted: 18 July 2012 / Published: 31 July 2012
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Abstract: Edema Factor (EF) is a component of Bacillus anthracis toxin essential for virulence. Its adenylyl cyclase activity is induced by complexation with the ubiquitous eukaryotic cellular protein, calmodulin (CaM). EF and its complexes with CaM, nucleotides and/or ions, have been extensively characterized by X-ray crystallography. Those structural data allowed molecular simulations analysis of various aspects of EF action mechanism, including the delineation of EF and CaM domains through their association energetics, the impact of calcium binding on CaM, and the role of catalytic site ions. Furthermore, a transition path connecting the free inactive form to the CaM-complexed active form of EF was built to model the activation mechanism in an attempt to define an inhibition strategy. The cavities at the surface of EF were determined for each path intermediate to identify potential sites where the binding of a ligand could block activation. A non-catalytic cavity (allosteric) was found to shrink rapidly at early stages of the path and was chosen to perform virtual screening. Amongst 18 compounds selected in silico and tested in an enzymatic assay, 6 thiophen ureidoacid derivatives formed a new family of EF allosteric inhibitors with IC50 as low as 2 micromolars.
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Received: 30 July 2012; in revised form: 8 October 2012 / Accepted: 10 October 2012 / Published: 19 October 2012
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Abstract: Bacillus anthracis secretes exotoxins which act through several mechanisms including those that can subvert adaptive immunity with respect both to antigen presenting cell and T cell function. The combination of Protective Antigen (PA) and Lethal Factor (LF) forming Lethal Toxin (LT), acts within host cells to down-regulate the mitogen activated protein kinase (MAPK) signaling cascade. Until recently the MAPK kinases were the only known substrate for LT; over the past few years it has become evident that LT also cleaves Nlrp1, leading to inflammasome activation and macrophage death. The predicted downstream consequences of subverting these important cellular pathways are impaired antigen presentation and adaptive immunity. In contrast to this, recent work has indicated that robust memory T cell responses to B. anthracis antigens can be identified following natural anthrax infection. We discuss how LT affects the adaptive immune response and specifically the identification of B. anthracis epitopes that are both immunogenic and protective with the potential for inclusion in protein sub-unit based vaccines.
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Received: 24 September 2012; in revised form: 25 October 2012 / Accepted: 1 November 2012 / Published: 8 November 2012
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Abstract: Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin’s basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC) in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera.
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Received: 24 November 2012; in revised form: 19 December 2012 / Accepted: 21 December 2012 / Published: 27 December 2012
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Abstract: Tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) are the two well-characterized anthrax toxin receptors, each containing a von Willebrand factor A (vWA) domain responsible for anthrax protective antigen (PA) binding. Recently, a cell-based analysis was used to implicate another vWA domain-containing protein, integrin β1 as a third anthrax toxin receptor. To explore whether proteins other than TEM8 and CMG2 function as anthrax toxin receptors in vivo, we challenged mice lacking TEM8 and/or CMG2. Specifically, we used as an effector protein the fusion protein FP59, a fusion between the PA-binding domain of anthrax lethal factor (LF) and the catalytic domain of Pseudomonas aeruginosa exotoxin A. FP59 is at least 50-fold more potent than LF in the presence of PA, with 2 μg PA + 2 μg FP59 being sufficient to kill a mouse. While TEM8−/− and wild type control mice succumbed to a 5 μg PA + 5 μg FP59 challenge, CMG2−/− mice were completely resistant to this dose, confirming that CMG2 is the major anthrax toxin receptor in vivo. To detect whether any toxic effects are mediated by TEM8 or other putative receptors such as integrin β1, CMG2−/−/TEM8−/− mice were challenged with as many as five doses of 50 μg PA + 50 μg FP59. Strikingly, the CMG2−/−/TEM8−/− mice were completely resistant to the 5-dose challenge. These results strongly suggest that TEM8 is the only minor anthrax toxin receptor mediating direct lethality in vivo and that other proteins implicated as receptors do not play this role.
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Received: 23 July 2012; in revised form: 29 September 2012 / Accepted: 17 December 2012 / Published: 14 January 2013
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Abstract: Inhaled Bacillus anthracis spores germinate and the subsequent vegetative growth results in bacteremia and toxin production. Anthrax toxin is tripartite: the lethal factor and edema factor are enzymatic moieties, while the protective antigen (PA) binds to cell receptors and the enzymatic moieties. Antibiotics can control B. anthracis bacteremia, whereas raxibacumab binds PA and blocks lethal toxin effects. This study assessed plasma PA kinetics in rabbits following an inhaled B. anthracis spore challenge. Additionally, at 84 h post-challenge, 42% of challenged rabbits that had survived were treated with either levofloxacin/placebo or levofloxacin/raxibacumab. The profiles were modeled using a modified Gompertz/second exponential growth phase model in untreated rabbits, with added monoexponential PA elimination in treated rabbits. Shorter survival times were related to a higher plateau and a faster increase in PA levels. PA elimination half-lives were 10 and 19 h for the levofloxacin/placebo and levofloxacin/raxibacumab groups, respectively, with the difference attributable to persistent circulating PA-raxibacumab complex. PA kinetics were similar between untreated and treated rabbits, with one exception: treated rabbits had a plateau phase nearly twice as long as that for untreated rabbits. Treated rabbits that succumbed to disease had higher plateau PA levels and shorter plateau duration than surviving treated rabbits.
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Received: 4 January 2013 / Accepted: 31 January 2013 / Published: 6 February 2013
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Abstract: The genes encoding Anthrax Toxin Receptors (ANTXRs) were originally identified based on expression in endothelial cells suggesting a role in angiogenesis. The focus of this review is to discuss what has been learned about the physiological roles of these receptors through evaluation of the Antxr knockout mouse phenotypes. Mice mutant in Antxr genes have defects in extracellular matrix homeostasis. We discuss how knowledge of physiological ANTXR function relates to what is already known about anthrax intoxication.
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Last update: 28 November 2011
