Neutralizing Monoclonal Antibody to Edema Toxin and Its Effect on Murine Anthrax

Winterroth, Lisa; Rivera, Johanna; Nakouzi, Antonio; Dadachova, Ekaterina; Casadevall, Arturo

doi:10.1128/iai.01101-09

Cited by 24 publications

(17 citation statements)

References 41 publications

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“…29 Previous attempts have shown, for example, that neutralizing polyclonal 41 and monoclonal 42,43 antibodies are protective against edema toxin challenge, and suggest a modest benefit in vivo during murine infection with the Sterne strain. 43 Clearly, the guinea pig model will help reassess the role of ET during infection. Inbred guinea pig strains are also available, facilitating immunological studies.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Imaging Technologies Reveal Edema Toxin as a Key Virulence Factor in Anthrax

Dumetz

Jouvion

Khun

et al. 2011

The American Journal of Pathology

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Powerful noninvasive imaging technologies enable realtime tracking of pathogen-host interactions in vivo, giving access to previously elusive events. We visualized the interactions between wild-type Bacillus anthracis and its host during a spore infection through bioluminescence imaging coupled with histology. We show that edema toxin plays a central role in virulence in guinea pigs and during inhalational infection in mice. Edema toxin (ET), but not lethal toxin (LT), markedly modified the patterns of bacterial dissemination leading, to apparent direct dissemination to the spleen and provoking apoptosis of lymphoid cells. Each toxin alone provoked particular histological lesions in the spleen. When ET and LT are produced together during infection, a specific temporal pattern of lesion developed, with early lesions typical of LT, followed at a later stage by lesions typical of ET. Our study provides new insights into the complex spatial and temporal effects of B. anthracis toxins in the infected host, suggesting a greater role than previously suspected for ET in anthrax and suggesting that therapeutic targeting of ET contributes to protection.

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Section: Discussionmentioning

confidence: 99%

Noninvasive Imaging Technologies Reveal Edema Toxin as a Key Virulence Factor in Anthrax

Dumetz

Jouvion

Khun

et al. 2011

The American Journal of Pathology

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“…Interestingly, mice immunized with vesicles produced more IgM than IgG (Fig. 4B) but immunization with purified toxins produces primarily IgG (26,27). We then evaluated the ability of unsonicated vesicles to elicit protective immunity by challenging vesicle-immunized mice with B. anthracis Sterne strain.…”

Section: Resultsmentioning

confidence: 99%

“…To estimate the percentage of free toxin in culture supernatants, we used two assays: capture ELISA and MTT cell assay of centrifuged and noncentrifuged supernatant fractions. We centrifuged the supernatant to remove vesicles, concentrated, and measured PA concentration by capture ELISA, as described (25,27). No soluble toxin was detected by capture ELISA in concentrated supernatants.…”

Section: Resultsmentioning

confidence: 99%

“…Monoclonal Ab 14FA γ2b is specific for LF of B. anthracis (22). Monoclonal Abs BD3 μ and FF7 γ1 are specific to EF (27). Monoclonal Abs 62F7 μ and 64F8 γ1 are specific for ALO of B. anthracis (38).…”

Section: Methodsmentioning

confidence: 99%

“…Isolated vesicles were solubilized in Laemmli sample buffer containing β-mercaptoethanol, boiled for 10 min, separated on a 12% SDS/PAGE, stained overnight with GelCode Blue Stain (Pierce), and visualized with ECL chemiluminescence kit (Pierce) (47). Membranes were incubated with either mAbs 10F4 IgG1 or BD3 IgM, as described (26,27).…”

Section: Measurement Of Vesicle Size By Qelsmentioning

confidence: 99%

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Bacillus anthracis produces membrane-derived vesicles containing biologically active toxins

Rivera¹,

Cordero²,

Nakouzi³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

340

345

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Extracellular vesicle production is a ubiquitous process in Gram-negative bacteria, but little is known about such process in Gram-positive bacteria. We report the isolation of extracellular vesicles from the supernatants of Bacillus anthracis, a Gram-positive bacillus that is a powerful agent for biological warfare. B. anthracis vesicles formed at the outer layer of the bacterial cell had double-membrane spheres and ranged from 50 to 150 nm in diameter. Immunoelectron microscopy with mAbs to protective antigen, lethal factor, edema toxin, and anthrolysin revealed toxin components and anthrolysin in vesicles, with some vesicles containing more than one toxin component. Toxin-containing vesicles were also visualized inside B. anthracis -infected macrophages. ELISA and immunoblot analysis of vesicle preparations confirmed the presence of B. anthracis toxin components. A mAb to protective antigen protected macrophages against vesicles from an anthrolysin-deficient strain, but not against vesicles from Sterne 34F2 and Sterne δT strains, consistent with the notion that vesicles delivered both toxin and anthrolysin to host cells. Vesicles were immunogenic in BALB/c mice, which produced a robust IgM response to toxin components. Furthermore, vesicle-immunized mice lived significantly longer than controls after B. anthracis challenge. Our results indicate that toxin secretion in B. anthracis is, at least, partially vesicle-associated, thus allowing concentrated delivery of toxin components to target host cells, a mechanism that may increase toxin potency. Our observations may have important implications for the design of vaccines, for passive antibody strategies, and provide a previously unexplored system for studying secretory pathways in Gram-positive bacteria.

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The role of sialic acid as a modulator of the anti-inflammatory activity of IgG

et al. 2012

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Immunoglobulin G (IgG) molecules can have two completely opposing activities. They can be very potent pro-inflammatory mediators on the one hand, directing the effector functions of the innate immune system towards infected cells, tumor cells or healthy tissues in the case of autoimmune diseases. On the other hand, a mixture of IgG molecules purified from the blood of ten thousands of healthy donors is used as an anti-inflammatory treatment for many autoimmune diseases since several decades. It has become evident only recently that certain residues in the sugar moiety attached to the IgG constant fragment can dramatically alter the pro- and anti-inflammatory activities of IgG. This review will focus on sialic acid residues as a modulator of the anti-inflammatory activity and provide an overview of situations where serum IgG glycosylation and sialylation is altered and which molecular and cellular pathways may be involved in this immunomodulatory pathway.

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Neutralizing Monoclonal Antibody to Edema Toxin and Its Effect on Murine Anthrax

Cited by 24 publications

References 41 publications

Noninvasive Imaging Technologies Reveal Edema Toxin as a Key Virulence Factor in Anthrax

Noninvasive Imaging Technologies Reveal Edema Toxin as a Key Virulence Factor in Anthrax

Bacillus anthracis produces membrane-derived vesicles containing biologically active toxins

The role of sialic acid as a modulator of the anti-inflammatory activity of IgG

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