Various forms of candidiasis plague our society, but our research over the past few years shows promise of vaccine development and antibody strategies against this opportunistic fungal disease. We have determined, in part, mechanisms of antibody protection against hematogenously disseminated candidiasis, but further studies are necessary to complete our understanding of mechanisms by which the antibodies protect against vaginal infection. We have structurally defined the key minimal oligomannoside epitope against which antibodies protect experimental animals against both hematogenously disseminated and vaginal forms of candidiasis, but a complete definition of the epitope should lead to more ideal vaccine formulations. We know that an oligomannoside without an appropriate protein carrier will not induce a protective antibody response, hence we propose to identify cell wall proteins that may serve a dual role as carrier and inducer of anti-protein protective responses. These studies should also lead to insights into the function of phosphomannoprotein complexes in Candida albicans cell walls. These various investigations will proceed by fulfillment of the following five specific aims: 1. Extend the studies on protective antibody/complement-dependency mechanisms involved in protection against hematogenously disseminated candidiasis by determining whether the entire complement cascade is necessary and whether the antibodies are protective in the absence of normal neutrophil and macrophage functions. 2. Determine whether antibody protection against vaginal infection involves complement. 3. Determine if bispecific antibodies that recognize both the beta-1,2-mannotriose and complement receptor on phagocytes are protective and do not require serum complement for protection. 4. Determine the complete epitope recognized by MAbs B6.1 (IgM) and C3.1 (IgG3). 5. Identify proteins N-linked to the phosphomannan complexes that display the beta-1,2-mannotriose, identify possible conjugate partners (carrier protein) for the phosphomannan vaccine formulation being developed on our P01 project and produce mutants to initiate studies into the function of these proteins.
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