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Revisiting the Concept of Targeting Only Bacillus anthracis Toxins as a Treatment for Anthrax.

ABSTRACT: Protective antigen (PA)-based vaccines are effective in preventing the development of fatal anthrax disease both in humans and in relevant animal models. The Bacillus anthracis toxins lethal toxin (lethal factor [LF] plus PA) and edema toxin (edema factor [EF] plus PA) are essential for the establishment of the infection, as inactivation of these toxins results in attenuation of the pathogen. Since the toxins reach high toxemia levels at the bacteremic stages of the disease, the CDC's recommendations include combining antibiotic treatment with antitoxin (anti-PA) immunotherapy. We demonstrate here that while treatment with a highly potent neutralizing monoclonal antibody was highly efficient as postexposure prophylaxis treatment, it failed to protect rabbits with any detectable bacteremia (?10 CFU/ml). In addition, we show that while PA vaccination was effective against a subcutaneous spore challenge, it failed to protect rabbits against systemic challenges (intravenous injection of vegetative bacteria) with the wild-type Vollum strain or a toxin-deficient mutant. To test the possibility that additional proteins, which are secreted by the bacteria under pathogenicity-stimulating conditions in vitro, may contribute to the vaccine's potency, we immunized rabbits with a secreted protein fraction from a toxin-null mutant. The antiserum raised against the secreted fraction reacts with the bacteria in an immunofluorescence assay. Immunization with the secreted protein fraction did not protect the rabbits against a systemic challenge with the fully pathogenic bacteria. Full protection was obtained only by a combined vaccination with PA and the secreted protein fraction. Therefore, these results indicate that an effective antiserum treatment in advanced stages of anthrax must include toxin-neutralizing antibodies in combination with antibodies against bacterial cell targets.

SUBMITTER: Glinert I

PROVIDER: S-EPMC4958181 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Revisiting the Concept of Targeting Only Bacillus anthracis Toxins as a Treatment for Anthrax.

Glinert Itai I Bar-David Elad E Sittner Assa A Weiss Shay S Schlomovitz Josef J Ben-Shmuel Amir A Mechaly Adva A Altboum Zeev Z Kobiler David D Levy Haim H

Antimicrobial agents and chemotherapy 20160722 8

Protective antigen (PA)-based vaccines are effective in preventing the development of fatal anthrax disease both in humans and in relevant animal models. The Bacillus anthracis toxins lethal toxin (lethal factor [LF] plus PA) and edema toxin (edema factor [EF] plus PA) are essential for the establishment of the infection, as inactivation of these toxins results in attenuation of the pathogen. Since the toxins reach high toxemia levels at the bacteremic stages of the disease, the CDC's recommenda ...[more]

PMID: 27270276

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Project description:BACKGROUND:Bacillus cereus biovar anthracis (Bcbva) is an emergent bacterium closely related to Bacillus anthracis, the etiological agent of anthrax. The latter has a worldwide distribution and usually causes infectious disease in mammals associated with savanna ecosystems. Bcbva was identified in humid tropical forests of Côte d'Ivoire in 2001. Here, we characterize the potential geographic distributions of Bcbva in West Africa and B. anthracis in sub-Saharan Africa using an ecological niche modeling approach. METHODOLOGY/PRINCIPAL FINDINGS:Georeferenced occurrence data for B. anthracis and Bcbva were obtained from public data repositories and the scientific literature. Combinations of temperature, humidity, vegetation greenness, and soils values served as environmental variables in model calibrations. To predict the potential distribution of suitable environments for each pathogen across the study region, parameter values derived from the median of 10 replicates of the best-performing model for each pathogen were used. We found suitable environments predicted for B. anthracis across areas of confirmed and suspected anthrax activity in sub-Saharan Africa, including an east-west corridor from Ethiopia to Sierra Leone in the Sahel region and multiple areas in eastern, central, and southern Africa. The study area for Bcbva was restricted to West and Central Africa to reflect areas that have likely been accessible to Bcbva by dispersal. Model predicted values indicated potential suitable environments within humid forested environments. Background similarity tests in geographic space indicated statistical support to reject the null hypothesis of similarity when comparing environments associated with B. anthracis to those of Bcbva and when comparing humidity values and soils values individually. We failed to reject the null hypothesis of similarity when comparing environments associated with Bcbva to those of B. anthracis, suggesting that additional investigation is needed to provide a more robust characterization of the Bcbva niche. CONCLUSIONS/SIGNIFICANCE:This study represents the first time that the environmental and geographic distribution of Bcbva has been mapped. We document likely differences in ecological niche-and consequently in geographic distribution-between Bcbva and typical B. anthracis, and areas of possible co-occurrence between the two. We provide information crucial to guiding and improving monitoring efforts focused on these pathogens.

Dataset Information

Revisiting the Concept of Targeting Only Bacillus anthracis Toxins as a Treatment for Anthrax.

Publications

Revisiting the Concept of Targeting Only Bacillus anthracis Toxins as a Treatment for Anthrax.

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