Anthrax Pathogenesis

Moayeri, Mahtab; Leppla, Stephen H.; Vrentas, Catherine E.; Pomerantsev, Andrei P.; Liu, Shihui

doi:10.1146/annurev-micro-091014-104523

Cited by 235 publications

(232 citation statements)

References 277 publications

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“…Anthrax toxins, together with an antiphagocytic polyglutamic capsule, are the bacterium's main virulence factors. Considered an occupational disease, it is rarely seen in high-income countries but is common in rural areas of low-and middleincome countries [1]. B.anthracis is a biological agent that may be used in bioterrorism attacks [2].…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of cutaneous anthrax in resource-poor settings in West Arsi Province, Ethiopia

Pérez‐Tanoira¹,

Ramos

Prieto-Pérez³

et al. 2017

Ann Agric Environ Med.

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Introduction. Cutaneous anthrax is a zoonotic disease caused by the spore-forming bacterium Bacillus anthracis, which typically presents with ulcers after contact with animals or animal products, and is rarely seen in high-income countries but is common in those with low-and middle-incomes. Objective. The aim of this study is to show the main clinical characteristics of cutaneous anthrax in endemic areas. Materials and method. The study describes the main clinical characteristics of cutaneous anthrax in eight patients (six female and two male, age range 1 -56 years) admitted to the rural General Hospital of Gambo, West Arsi Province of Ethiopia from 2010-2013. Results. In all cases, lesions began as an erythematous papule located on exposed sites (n=7 head; n=1 thigh) and subsequently became a necrotic black eschar surrounded by an edematous halo. Two patients presented with painful ipsilateral adenopathy near the black eschar. Four patients developed a malignant pustule on the suborbital region of the face. Patients responded positively to treatment, and the lesions resolved, leaving eschars. However, one patient suffered the loss of an eyeball, and another died 12 hours after starting treatment. Conclusions. Physicians working in rural areas of resource-poor settings should be trained in the clinical identification of cutaneous anthrax. Early antibiotic treatment is essential for decreasing morbidity and mortality.

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Section: Introductionmentioning

confidence: 99%

Diagnosis of cutaneous anthrax in resource-poor settings in West Arsi Province, Ethiopia

Pérez‐Tanoira¹,

Ramos

Prieto-Pérez³

et al. 2017

Ann Agric Environ Med.

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“…which are released from Bacillus anthracis as monomers and assemble into toxic complexes on the surface of animal cells (1)(2)(3). PA is the moiety which binds to cell surface receptors and facilitates entry of the enzymatic EF and LF moieties into the host cell cytosol.…”

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confidence: 99%

Anthrax Toxin Protective Antigen Variants That Selectively Utilize either the CMG2 or TEM8 Receptors for Cellular Uptake and Tumor Targeting

Chen

Liu

Leysath

et al. 2016

Journal of Biological Chemistry

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The protective antigen (PA) moiety of anthrax toxin binds to cellular receptors and mediates the translocation of the two enzymatic moieties of the toxin to the cytosol. Two PA receptors are known, with capillary morphogenesis protein 2 (CMG2) being the more important for pathogenesis and tumor endothelial marker 8 (TEM8) playing a minor role. The C-terminal PA domain 4 (PAD4) has extensive interactions with the receptors and is required for binding. Our previous study identified PAD4 variants having enhanced TEM8 binding specificity. To obtain PA variants that selectively bind to CMG2, here we performed phage display selections using magnetic beads having bound CMG2. We found that PA residue isoleucine 656 plays a critical role in PA binding to TEM8 but has a much lesser effect on PA binding to CMG2. We further characterized the role of residue 656 in distinguishing PA binding to CMG2 versus TEM8 by substituting it with the other 19 amino acids. Of the resulting variants, PA I656Q and PA I656V had significantly reduced activity on TEM8-expressing CHO cells but maintained their activity on CMG2-expressing CHO cells. The preference of these PA mutants for CMG2 over TEM8 was further demonstrated using mouse embryonic fibroblast cells and mice deficient in the CMG2 and/or the TEM8 receptors. The structural basis of the alterations in the receptor binding activities of these mutants is also discussed.Anthrax toxin is composed of three nontoxic proteins: protective antigen (PA), 3 lethal factor (LF), and edema factor (EF), which are released from Bacillus anthracis as monomers and assemble into toxic complexes on the surface of animal cells (1-3). PA is the moiety which binds to cell surface receptors and facilitates entry of the enzymatic EF and LF moieties into the host cell cytosol. Two anthrax toxin receptors have been identified; capillary morphogenesis protein 2 (CMG2, or anthrax toxin receptor 2) is the physiologically relevant toxin receptor mediating most of the in vivo toxicity of the toxin, whereas tumor endothelial marker 8 (TEM8, or anthrax toxin receptor 1) functions only as a minor anthrax toxin receptor (4 -8). Upon binding to the toxin receptors, PA is cleaved at the sequence 164 RKKR 167 by cell surface furin or furin-like proteases (9, 10), yielding the C-terminal 63-kDa fragment (PA63), which assembles to form a ring-shaped oligomer. The PA63 oligomer then binds LF and/or EF, and the toxin complex is internalized by receptor-mediated endocytosis. LF and EF are translocated into the cytosol from early or late endosomes to exert their cytotoxic effects. Therefore, PA plays the crucial role in anthrax toxin pathogenesis, serving as the delivery vehicle for translocation of LF and EF into the cytosol of the cell.The absolute requirement for cell surface proteolytic activation of PA for the toxin's action prompted our group and others to reengineer PA to make it depend on tumor-associated proteases for activation, thereby achieving high specificity for tumors (11)(12)(13)(14)(15). In a recent example, ...

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“…B. anthracis causes 3 forms of anthrax, cutaneous, gastrointestinal and inhalation-derived infections. 1 Anthrax has been well characterized throughout history; documented cases date back prior to 450 BCE. 2 Vaccine development for anthrax began in the 1880s with attenuated strains developed by Pasteur in France and Greenfield in London.…”

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confidence: 99%

“…Live attenuated B. anthracis vaccines are no longer used for human immunizations. 1,4 Attenuated strains of B. anthracis have been shown to provide immunological protection from virulent strains, but only if the bacterial toxins are present.…”

mentioning

confidence: 99%

“…6 Once the resulting polypeptides are expressed, they combine to form 2 binary toxins known as lethal toxin and edema toxin, which are responsible for the extensive tissue destruction in anthrax. 1 In addition to its role in toxin formation, PA is also recognized as a potent immunogen, critical to the development of a protective immune response. 3 The pXO2 plasmid is roughly 96 kb and carries the genes responsible for expression and formation of the polyg-D-glutamic acid (PGA) capsule.…”

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confidence: 99%

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