The Effects of Anthrax Toxin Components on Human Neutrophils Infection and Immunity

Friedlander, A. M.; Drier, T.; Ezzell, Johnw .; Leppla, Stephenh .

doi:10.21236/ada144757

Cited by 76 publications

(95 citation statements)

References 10 publications

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“…The lethal and edema toxins are thought to interfere with macrophage function, although their role in intracellular killing and the fate of B. anthracis itself in macrophages remain unclear, with either killing (60), persistence (18), or growth (10) being reported, which is likely related to methodological differences and the use of different cells and bacterial strains, both encapsulated and unencapsulated. The toxins have also been reported to interfere with neutrophil function (1,13,23,39,61), while capsule synthesis and encapsulation renders the bacillus resistant to phagocytosis when tested in vitro (23,30,49) (Table 1), and in infected animals, encapsulated bacilli are essentially observed only extracellularly (9). With host innate immune defenses compromised, the bacteria grow to levels as high as 10 8 to 10 9 CFU/ml in the blood.…”

Section: Discussionmentioning

confidence: 99%

Poly-γ-Glutamate Capsule-Degrading Enzyme Treatment Enhances Phagocytosis and Killing of EncapsulatedBacillus anthracis

Scorpio

Chabot

Day

et al. 2007

Antimicrob Agents Chemother

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The poly-␥-D-glutamic acid capsule confers antiphagocytic properties on Bacillus anthracis and is essential for virulence. In this study, we showed that CapD, a ␥-polyglutamic acid depolymerase encoded on the B. anthracis capsule plasmid, degraded purified capsule and removed the capsule from the surface of anthrax bacilli. Treatment with CapD induced macrophage phagocytosis of encapsulated B. anthracis and enabled human neutrophils to kill encapsulated organisms. A second glutamylase, PghP, a ␥-polyglutamic acid hydrolase encoded by Bacillus subtilis bacteriophage ⌽NIT1, had minimal activity in degrading B. anthracis capsule, no effect on macrophage phagocytosis, and only minimal enhancement of neutrophil killing. Thus, the levels of both phagocytosis and killing corresponded to the degree of enzyme-mediated capsule degradation. The use of enzymes to degrade the capsule and enable phagocytic killing of B. anthracis offers a new approach to the therapy of anthrax.

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Section: Discussionmentioning

confidence: 99%

Poly-γ-Glutamate Capsule-Degrading Enzyme Treatment Enhances Phagocytosis and Killing of EncapsulatedBacillus anthracis

Scorpio

Chabot

Day

et al. 2007

Antimicrob Agents Chemother

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“…Escherichia coli containing the gene for streptococcal pyrogenic exotoxin A (speA) in a pET28b vector was the source of the superantigen SPE A (3). The Sterne strain was the source of culture fluids containing B. anthracis hemolysins and anthrax toxin (a mixture of protective antigen, lethal factor, and edema factor) (28), and Group A streptococcal strain T18P was the source of culture fluids containing the hemolysins streptolysins O and S (29). All strains are maintained in the laboratory in the lyophilized state.…”

Section: Bacteria Exotoxins and Chemicalsmentioning

confidence: 99%

Glycerol Monolaurate Inhibits the Effects of Gram-Positive Select Agents on Eukaryotic Cells

Peterson

Schlievert

2006

Biochemistry

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Many exotoxins of gram positive bacteria, such as superantigens (staphylococcal enterotoxins, toxic shock syndrome toxin-1 [TSST-1], and streptococcal pyrogenic exotoxins) and anthrax toxin are bioterrorism agents that cause diseases by immunostimulation or cytotoxicity. Glycerol monolaurate (GML), a fatty acid monoester found naturally in humans, has been reported to prevent synthesis of gram positive bacterial exotoxins. This study explored the ability of GML to inhibit the effects of exotoxins on mammalian cells and prevent rabbit lethality from TSS. GML (≥10 ug/ml) inhibited superantigen (5 ug/ml) immunoproliferation, as determined by inhibition of 3 H-thymidine incorporation into DNA of human peripheral blood mononuclear cells (1 × 10 6 cells/ml) as well as phospholipase Cγ1, suggesting inhibition of signal transduction. The compound (20 ug/ml) prevented superantigen (100 ug/ml) induced cytokine secretion by human vaginal epithelial cells (HVECs) as measured by ELISA. GML (250 ug) inhibited rabbit lethality due to TSST-1 administered vaginally. GML (10 ug/ml) inhibited HVEC and macrophage cytotoxicity by anthrax toxin, prevented erythrocyte lysis by purified hemolysins (staphylococcal α and β) and culture fluids containing streptococcal and Bacillus anthracis hemolysins, and was non-toxic to mammalian cells (up to 100 ug/ml) and rabbits (250 ug). GML stabilized mammalian cell membranes, as erythrocyte lysis was reduced in the presence of hypotonic aqueous solutions (0 to 0.05 M saline) or staphylococcal α and β-hemolysins when erythrocytes were pretreated with GML. GML may be useful in management of gram positive exotoxin illnesses; its action appears to be membrane stabilization with inhibition of signal transduction.Many gram positive bacterial pathogens produce exotoxins that are potential agents of bioterrorism and contribute to their abilities to cause human diseases (1-3). Examples include anthrax toxin made by Bacillus anthracis (2), superantigens produced by Staphylococcus aureus, including staphylococcal enterotoxins (SEs) 1 and toxic shock syndrome toxin-1 (TSST-1) (1), and superantigens produced by group A streptococci, including streptococcal pyrogenic exotoxins (SPEs) (3). Other exotoxins, such as staphylococcal α and β-hemolysins and streptolysins, are not agents of bioterrorism but have adjunct roles in virulence and can be used as model toxins to study mechanisms of cellular toxicity.

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“…The capsule is essential for virulence (3,10,18,21), and its antiphagocytic property is a primary mechanism of immune cell evasion utilized by B. anthracis (21,22,26). The anthrax lethal toxin (PA plus LF) and edema toxin (PA plus EF) are known to inhibit some neutrophil functions (1,8,12,21,34,43), but in contrast to a deleterious effect of lethal toxin on macrophage survival from some animals (13,14), neither affects human neutrophil viability (8). Methods to counter the antihost properties of the capsule and toxins represent current areas of anthrax research and may lead to new vaccines and treatments.…”

mentioning

confidence: 99%

Treatment of Experimental Anthrax with Recombinant Capsule Depolymerase

Scorpio

Tobery

Ribot

et al. 2008

Antimicrob Agents Chemother

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Bacillus anthracis produces an antiphagocytic gamma-linked poly-D-glutamic acid capsule that is required for virulence. Capsule depolymerase (CapD) is a membrane-associated poly-␥-glutamate-specific depolymerase encoded on the B. anthracis capsule plasmid, pX02, that is reported to contribute to virulence by anchoring the capsule to the peptidoglycan and partially degrading high-molecular-weight capsule from the bacterial surface. We previously demonstrated that treatment with CapD effectively removes the capsule from anthrax bacilli, rendering them susceptible to phagocytic killing in vitro. Here we report that CapD promoted in vivo phagocytic killing of B. anthracis bacilli by mouse peritoneal neutrophils and that parenteral administration of CapD protected mice in two models of anthrax infection. CapD conferred significant protection compared with controls when coinjected with encapsulated bacilli from fully virulent B. anthracis Ames or the nontoxigenic encapsulated strain ⌬Ames and when injected 10 min after infection with encapsulated bacilli from B. anthracis Ames. Protection was also observed when CapD was administered 30 h after infection with B. anthracis ⌬Ames spores, while significant protection could not be demonstrated following challenge with B. anthracis Ames spores. These data support the proposed role of capsule in B. anthracis virulence and suggest that strategies to target anthrax bacilli for neutrophil killing may lead to novel postexposure therapies.

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The Effects of Anthrax Toxin Components on Human Neutrophils Infection and Immunity

Cited by 76 publications

References 10 publications

Poly-γ-Glutamate Capsule-Degrading Enzyme Treatment Enhances Phagocytosis and Killing of EncapsulatedBacillus anthracis

Poly-γ-Glutamate Capsule-Degrading Enzyme Treatment Enhances Phagocytosis and Killing of EncapsulatedBacillus anthracis

Glycerol Monolaurate Inhibits the Effects of Gram-Positive Select Agents on Eukaryotic Cells

Treatment of Experimental Anthrax with Recombinant Capsule Depolymerase

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