While potent antifungal agents exist that are microbicidal for Candida, the attributable mortality of candidemia is approximately 38%, even with currently available antifungal therapy. The use of either passive or active immuno-therapy against Candida is a promising alternative to standard anti- fungal therapy of its potential to avoid the problems association with heavy use of antifungal agents. Our long range goal is to identify dominant candidal adhesions and use these adhesions as targets for active or passive immunotherapy for serious candidal infections. During the current project period, we determined that the C. albicans gene, ALS1, likely encodes an adhesin that mediated attachment to endothelial and epithelial cells. This gene is a member of the ALS gene family. To date, approximately 11 members of the ALS gene family have been identified. However, the sequence of only two of these genes have been published. It is our central hypothesis that the ALS gene family encodes the major adhesion of C. albicans. It is likely that the different ALS proteins mediate adherence to different host constituent ligands. We propose to systematically examine selected members of the ALS gene family to determine which of them encode adhesins that mediate the binding of C. albicans to endothelium epithelium, and other host constituents. This information will be used to develop techniques to block the adherence of the organism to host tissues by using either passive or active immunization.
The Specific Aims for this project are to i) obtain thje full-length sequence of ALS6 and ALS94-98; ii) determine if the above ALS genes encode adhesions to endothelial cells, epithelial cells and selected other host constituents, and determine the ligands on the cell surface to which they bind; iii) determine if antibodies against specific ALS proteins block the adherence of C. albicans to endothelial and epithelial cells, and the selected host constituents in vitro; and iv) determine if antibodies against specific ALS proteins protect mice from mucosal and hematogenously disseminated candidal infections. We will identify adhesion as targets for active and passive immunization strategies. These adhesins are highly attractive targets for immunotherapy by themselves, have the potential to be used in combination with the targets identified by other projects in the Mycology Research Unit.
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