This proposal for a Mycology Research Unit (MRU) is focused on a comprehensive effort to identify and evaluate the ability the ability of candidate antigens to produce protective immunity against hematogenously disseminated candidiasis. The driving forces behind this effort are the high frequency of candidal infections, the attractiveness of a future DNA vaccine strategy, and the need for treatment approaches that will minimize the development of antifungal resistance. Project 1 builds on the discovery during the current grant period that antibody response to certain epitopes of the phosphomannan complex of C. albicans enhances resistance to experimental disseminated candidiasis. Approaches for the proposed period include: i) use of stabilized liposomal constructs to improve the liposomal vaccine formulations, ii) production of protein conjugates of the critical mannan epitopes, and iii) construction of a DNA vaccine based on peptide mimotopes of the """"""""protective"""""""" mannan epitopes. Project 2 is based on the central hypothesis that the ASL (agglutinin mimotopes of the """"""""protective"""""""" mannan epitopes. Project 2 is based on the central hypothesis that the ASL (agglutinin like sequence) gene family of Candida contains genes that encode dominant adhesions of Candida for a variety of host constituents. Gene products of the ALS gene family will be evaluated as potential vaccine targets for both active and passive immunization. The active immunization will be accomplished using DNA vaccine approaches and may be used in combination with phosphomannan antigens identified in project 1 to optimize an immune response. Project 3 will utilize the ability of affinity-purify large amounts of anti-mannan antibodies from human plasma to directly test the biological activities of these antibodies and the contribution to protection of the fine epitope specificity of human anti-mannan antibody. Project 4 utilizes highly innovative molecular biology strategies to identify yet undiscovered cell surface proteins that may be attractive vaccine targets. Genes that are expressed during infection will be identified by screening of random fusion genes. Comparison of functional sequences to the C. albicans genomic sequence will permit identification of likely secreted, cell wall, and transmembrane proteins, available for interaction with antibody. These gene products can then be used either alone or in combination with other target immunogens to develop effective vaccines. This technology lends itself well to the incorporation of multiple candidate immunogens into DNA vaccines.
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