Bacillus anthracis, the causative agent of anthrax, produces two bipartite toxins (lethal and edema toxin). These toxins contribute a large portion of the pathogenesis of this organism; therefore, the common component of both toxins (protective antigen) is the primary antigen in vaccination regimens. Previous research has indicated that immunization with both protein components of lethal toxin (lethal factor and protective antigen) increases antibody response to each component. In this work, the functional activities of lethal toxin were investigated in order to identify the toxin actions producing the enhanced immune response. Each step of the cellular intoxication process was examined, as was the catalytic activity of lethal toxin. Single amino acid changes were introduced into each lethal toxin component in order to remove specific functional activities. The immune responses generated by toxin combinations lacking a single functional activity were then compared to the response stimulated by wild type lethal toxin. The enhanced antibody response to lethal toxin depended on its catalytic activity. Although the inactive forms of lethal toxin did not produce an increase in antibody titer, altering the intoxication ability of lethal toxin revealed an underlying competition between the immune responses to protective antigen and lethal factor. The antibody response to lethal factor depended on the production of IFN-γ and the cytosolic localization of this antigen. In contrast, the antibody response to protective antigen produced large amounts of IL-4. The resulting antagonism between these two cytokines led to competition under all circumstances tested. Antibody production was also enhanced by combining the edema toxin components (protective antigen and edema factor). Despite structural similarities to lethal toxin, edema toxin had a different interaction with the immune system. The combination of edema toxin components acted as an adjuvant and stimulated an increase in antibody titers. This increase did not depend on either the catalytic activity of edema toxin or the cellular intoxication process. Competition between the antibody responses against the edema toxin components was observed only when edema factor was localized to the cytosol and separated from protective antigen; otherwise the humoral response to both proteins was enhanced.
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Anthrax, Bacillus anthracis, Edema toxin, Lethal toxin, Protective antigen, Vaccine|
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