Infectious agents with biological weapon potential have become the focus of intense interest since the terrorist events of September 11, 2001 and the subsequent anthrax attacks. One area of proposed focus is to meld the experience of human immunologists with category A pathogen biologists to understand in detail the primary immune targets of potential pathogenic targets of bioterrorism. This proposal seeks to understand the humoral immune response to Bacillis anthracis through a collaborative project of human immunologists and an anthrax biologist. Over the past 15 years, the PI's laboratory has focused on defining the sequential antigenic B cell determinants of various autoimmune responses (1-24). Interestingly, we have also proven that this method of B cell epitope mapping works well for characterization of the immune response to pathogenic organisms (25-29 and unpublished observations). By understanding the fine specificity of these responses we have been able to define the initial epitope of specific lupus response, to determine and test association with potential environmental triggers of these responses and to induce lupus-like disease by animal immunization schemes. We now propose to utilize our extensive expertise in protein chemistry, fine specificity mapping, epitope confirmation, molecular modeling and animal immunization to identify the common B cell antigenic targets of Bacillus anthracis. Dr. Farris' experience with murine cellular immunology, including multiple antigenic peptide immunization (30) and dendritic cell biology (Preliminary Studies) will contribute to our evaluation of the identified epitopes for potential prophylactic and treatment value. In addition, this project will utilize the anthrax-specific reagents and experience of our co-investigator, Dr. Jimmy Ballard. We will use our modified solid phase peptide approach to build over 2700 maximally overlapping octapeptides and screen exposed individual and animal sera for common sequential epitopes. These antigenic regions will be confirmed by a separate fluid phase ELISA and the total percent of the immune response to the parent antigen comprised of detected anti-peptide reactivity will be determined. These novel antigenic epitopes will be screened for their ability to induce (1) neutralizing and spore germination inhibiting antibodies, (2) restoration of B. anthracis subverted phagocyte function and (3) protection in animals challenged with live spores.
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