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Recombinant HSA-CMG2 Is a Promising Anthrax Toxin Inhibitor

by Liangliang Li, Qiang Guo, Ju Liu, Jun Zhang, Ying Yin, Dayong Dong, Ling Fu, Junjie Xu and Wei Chen

Toxins 2016, 8(1), 28; https://doi.org/10.3390/toxins8010028 - 20 Jan 2016

Cited by 5 | Viewed by 5802

Abstract

Anthrax toxin is the major virulence factor produced by Bacillus anthracis. Protective antigen (PA) is the key component of the toxin and has been confirmed as the main target for the development of toxin inhibitors. The inhibition of the binding of PA to its receptor, capillary morphogenesis protein-2 (CMG2), can effectively block anthrax intoxication. The recombinant, soluble von Willebrand factor type A (vWA) domain of CMG2 (sCMG2) has demonstrated potency against anthrax toxin. However, the short half-life of sCMG2 in vivo is a disadvantage for its development as a new anthrax drug. In the present study, we report that HSA-CMG2, a protein combining human serum albumin (HSA) and sCMG2, produced in the Pichia pastoris expression system prolonged the half-life of sCMG2 while maintaining PA binding ability. The IC₅₀ of HSA-CMG2 is similar to those of sCMG2 and CMG2-Fc in in vitro toxin neutralization assays, and HSA-CMG2 completely protects rats from lethal doses of anthrax toxin challenge; these same challenge doses exceed sCMG2 at a sub-equivalent dose ratio and overwhelm CMG2-Fc. Our results suggest that HSA-CMG2 is a promising inhibitor of anthrax toxin and may contribute to the development of novel anthrax drugs. Full article

(This article belongs to the Collection Anthrax Toxins)

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12 pages, 838 KiB

Open AccessArticle

Cell-to-Cell Propagation of the Bacterial Toxin CNF1 via Extracellular Vesicles: Potential Impact on the Therapeutic Use of the Toxin

by Alessia Fabbri, Sara Cori, Cristiana Zanetti, Marco Guidotti, Massimo Sargiacomo, Stefano Loizzo and Carla Fiorentini

Toxins 2015, 7(11), 4610-4621; https://doi.org/10.3390/toxins7114610 - 5 Nov 2015

Cited by 8 | Viewed by 5351

Abstract

Eukaryotic cells secrete extracellular vesicles (EVs), either constitutively or in a regulated manner, which represent an important mode of intercellular communication. EVs serve as vehicles for transfer between cells of membrane and cytosolic proteins, lipids and RNA. Furthermore, certain bacterial protein toxins, or possibly their derived messages, can be transferred cell to cell via EVs. We have herein demonstrated that eukaryotic EVs represent an additional route of cell-to-cell propagation for the Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1). Our results prove that EVs from CNF1 pre-infected epithelial cells can induce cytoskeleton changes, Rac1 and NF-κB activation comparable to that triggered by CNF1. The observation that the toxin is detectable inside EVs derived from CNF1-intoxicated cells strongly supports the hypothesis that extracellular vesicles can offer to the toxin a novel route to travel from cell to cell. Since anthrax and tetanus toxins have also been reported to engage in the same process, we can hypothesize that EVs represent a common mechanism exploited by bacterial toxins to enhance their pathogenicity. Full article

(This article belongs to the Section Bacterial Toxins)

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13 pages, 3837 KiB

Open AccessArticle

The Saccharomyces boulardii CNCM I-745 Strain Shows Protective Effects against the B. anthracis LT Toxin

by Rodolphe Pontier-Bres, Patrick Rampal, Jean-François Peyron, Patrick Munro, Emmanuel Lemichez and Dorota Czerucka

Toxins 2015, 7(11), 4455-4467; https://doi.org/10.3390/toxins7114455 - 30 Oct 2015

Cited by 9 | Viewed by 8705

Abstract

The probiotic yeast Saccharomyces boulardii (S. boulardii) has been prescribed for the prophylaxis and treatment of several infectious diarrheal diseases. Gastrointestinal anthrax causes fatal systemic disease. In the present study, we investigated the protective effects conferred by Saccharomyces boulardii CNCM I-745 strain on polarized T84 columnar epithelial cells intoxicated by the lethal toxin (LT) of Bacillus anthracis. Exposure of polarized T84 cells to LT affected cell monolayer integrity, modified the morphology of tight junctions and induced the formation of actin stress fibers. Overnight treatment of cells with S. boulardii before incubation with LT maintained the integrity of the monolayers, prevented morphological modification of tight junctions, restricted the effects of LT on actin remodeling and delayed LT-induced MEK-2 cleavage. Mechanistically, we demonstrated that in the presence of S. boulardii, the medium is depleted of both LF and PA sub-units of LT and the appearance of a cleaved form of PA. Our study highlights the potential of the S. boulardii CNCM I-745 strain as a prophylactic agent against the gastrointestinal form of anthrax. Full article

(This article belongs to the Collection Anthrax Toxins)

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14 pages, 500 KiB

Open AccessArticle

Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge

by T. Scott Devera, Dawn K. Prusator, Sunil K. Joshi, Jimmy D. Ballard and Mark L. Lang

Toxins 2015, 7(7), 2371-2384; https://doi.org/10.3390/toxins7072371 - 25 Jun 2015

Cited by 3 | Viewed by 5880

Abstract

Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand α-galactosylceramide (αGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities. Full article

(This article belongs to the Collection Anthrax Toxins)

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12 pages, 484 KiB

Open AccessReview

Studies in Mice Reveal a Role for Anthrax Toxin Receptors in Matrix Metalloproteinase Function and Extracellular Matrix Homeostasis

by Claire Reeves, Pelisa Charles-Horvath and Jan Kitajewski

Toxins 2013, 5(2), 315-326; https://doi.org/10.3390/toxins5020315 - 6 Feb 2013

Cited by 11 | Viewed by 6005

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. Full article

(This article belongs to the Special Issue Anthrax Toxin)

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20 pages, 1088 KiB

Open AccessReview

Antibodies against Anthrax: Mechanisms of Action and Clinical Applications

by Jeffrey W. Froude II, Philippe Thullier and Thibaut Pelat

Toxins 2011, 3(11), 1433-1452; https://doi.org/10.3390/toxins3111433 - 16 Nov 2011

Cited by 29 | Viewed by 10043

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. Full article

(This article belongs to the Special Issue Anthrax Toxin)

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12 pages, 422 KiB

Open AccessReview

T Cell Targeting by Anthrax Toxins: Two Faces of the Same Coin

by Silvia Rossi Paccani and Cosima T. Baldari

Toxins 2011, 3(6), 660-671; https://doi.org/10.3390/toxins3060660 - 20 Jun 2011

Cited by 15 | Viewed by 10429

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. Full article

(This article belongs to the Special Issue Anthrax Toxin)

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