Association of
            <i>Bacillus anthracis</i>
            Capsule with Lethal Toxin during Experimental Infection

Ezzell, John W.; Abshire, Teresa G.; Panchal, Rekha G.; Chabot, Donald J.; Bavari, Sina; Leffel, Elizabeth K.; Purcell, Bret K.; Friedlander, Arthur M.; Ribot, Wilson J.

doi:10.1128/iai.00764-08

Cited by 35 publications

(38 citation statements)

References 35 publications

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“…γDPGA not only is found on the surface of vegetative bacteria but also has also been reported to occur in a soluble form during the systemic phase of the infection (19). Some of the soluble γDPGA was found to be associated with lethal toxin, raising the possibility that γDPGA may play a novel and unexpected role in anthrax pathogenesis (25). Therefore, anti-γDPGA mAbs may have protective effects that extend beyond their demonstrated ability to promote opsonophagocytic killing of bacteria.…”

Section: Discussionmentioning

confidence: 99%

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Chen¹,

Schneerson

Lovchik

et al. 2010

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

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One of the two essential virulence factors of Bacillus anthracis is the poly-γ-D-glutamic acid (γDPGA) capsule. Five γDPGA-specific antibody antigen-binding fragments (Fabs) were generated from immunized chimpanzees. The two selected for further study, Fabs 11D and 4C, were both converted into full-length IgG1 and IgG3 mAbs having human IgG1 or IgG3 constant regions. These two mAbs had similar binding affinities, in vitro opsonophagocytic activities, and in vivo efficacies, with the IgG1 and IgG3 subclasses reacting similarly. The mAbs bound to γDPGA specifically with estimated binding affinities (K d ) of 35-70 nM and effective affinities (effective K d ) of 0.1-0.3 nM. The LD 50 in an opsonophagocytic bactericidal assay was ≈10 ng/mL of 11D or 4C. A single 30-μg dose of either mAb given to BALB/c mice 18 h before challenge conferred about 50% protection against a lethal intratracheal spore challenge by the virulent B. anthracis Ames strain. More importantly, either mAb given 8 h or 20 h after challenge provided significant protection against lethal infection. Thus, these anti-γDPGA mAbs should be useful, alone or in combination with antitoxin mAbs, for achieving a safe and efficacious postexposure therapy for anthrax.

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Section: Discussionmentioning

confidence: 99%

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Chen¹,

Schneerson

Lovchik

et al. 2010

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

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“…The γ-DPGA capsule produced by B. anthracis constitutes the other key virulence factor of anthrax disease. A recent report revealed that γ-DPGA and lethal toxin may interact (27). Also, 10-50-kDa fragments of γ-DPGA were reported to enhance LT-mediated killing of J774A.1 cells (29).…”

Section: D2-d4 Interface Senses Capsule and Protons During Channelmentioning

confidence: 99%

“…Whereas the PA monomer, LF, and EF can bind to capsule, the PA prechannel oligomer binds most avidly to the capsule in the nanomolar range. In vivo, only preassembled LT, LF, and proteolytically active PA 63 (and not full-length PA 83 ) are observed in the plasma (27); however, for these fractions of the toxin to function, they must be assembled, stabilized, and capable of sensing their environment. The stabilization of PA prechannels by γ-DPGA may maintain their thermostability in vivo, because premature channel formation inactivates the toxin (10).…”

Section: D2-d4 Interface Senses Capsule and Protons During Channelmentioning

confidence: 99%

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Anthrax toxin protective antigen integrates poly-γ- d -glutamate and pH signals to sense the optimal environment for channel formation

Kintzer

Tang²,

Schawel³

et al. 2012

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

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Many toxins assemble into oligomers on the surface of cells. Local chemical cues signal and trigger critical rearrangements of the oligomer, inducing the formation of a membrane-fused or channel state. Bacillus anthracis secretes two virulence factors: a tripartite toxin and a poly-γ-D-glutamic acid capsule (γ-DPGA). The toxin's channel-forming component, protective antigen (PA), oligomerizes to create a prechannel that forms toxic complexes upon binding the two other enzyme components, lethal factor (LF) and edema factor (EF). Following endocytosis into host cells, acidic pH signals the prechannel to form the channel state, which translocates LF and EF into the host cytosol. We report γ-DPGA binds to PA, LF, and EF, exhibiting nanomolar avidity for the PA prechannel oligomer. We show PA channel formation requires the pH-dependent disruption of the intra-PA domain-2-domain-4 (D2-D4) interface. γ-DPGA stabilizes the D2-D4 interface, preventing channel formation both in model membranes and cultured mammalian cells. A 1.9-Å resolution X-ray crystal structure of a D2-D4-interface mutant and corresponding functional studies reveal how stability at the intra-PA interface governs channel formation. We also pinpoint the kinetic pH trigger for channel formation to a residue within PA's membrane-insertion loop at the inter-PA D2-D4 interface. Thus, γ-DPGA may function as a chemical cue, signaling that the local environment is appropriate for toxin assembly but inappropriate for channel formation.pH sensor | translocation | planar bilayer electrophysiology

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“…More importantly, industrial production of c-PGA from B. anthracis is not viable owing to its toxicity. In fact, the anchored c-PGA is responsible for the non-immunogenic capsule of B. anthracis, which has been associated with the lethal toxin (Ezzell et al, 2009). Hence, to render B. anthracis immunogenic, its cap gene responsible for the anchoring of c-PGA onto its surface needs to be targeted (Candela & Fouet, 2006).…”

Section: Other Bacteriamentioning

confidence: 99%

Poly-γ-glutamic acid: production, properties and applications

et al. 2015

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Association of Bacillus anthracis Capsule with Lethal Toxin during Experimental Infection

Abstract: Bacillus anthracis lethal toxin (LT) was characterized in plasma from infected

Cited by 35 publications

References 35 publications

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Anthrax toxin protective antigen integrates poly-γ- d -glutamate and pH signals to sense the optimal environment for channel formation

Poly-γ-glutamic acid: production, properties and applications

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