Nationwide, bloodstream infections with Candida species have increased by 219-48% between 1980-1989, and these organisms now account for 10% of all nosocomial bloodstream isolates. This incidence equals that of Escherichia coli and surpasses Klebsiella species. In addition to hematogenously disseminated candidal infections, mucocutaneous candidal infections are becoming increasingly problematic, especially in patients with the acquired immunodeficiency syndrome (AIDS); 80% of these patients have candidal infections. Adherence to epithelial cells is the first step in colonization by Candida and subsequent establishment of mucocutaneous infection. Similarly, adherence to intravascular structures is considered to be a critical step in the egress of blood- borne fungi from the intravascular compartment, as they hematogenously infect target organs. Because the mortality rates associated with candidal infections remain disturbingly high despite the presence of antifungal agents with excellent in vitro activity against Candida, optimal therapy requires strategies to increase host resistance to candidal infection (such as blocking adherence), combined with the use of antifungal agents. After more than two decades of study, a single integrated understanding of the adhesive process in candidiasis has not evolved. Project 1 will use transformation of candidal genomic DNA into Saccharomyces cerevisiae and assays of expression of candidal gene products at the surface of S. cerevisiae to identify candidal adhesins. Project 2 will use novel in vitro adhesion assays done under physiologic shear conditions to study C. albicans adhesive interactions which take place during blood flow. Project 3 will investigate a vaccine induced alteration in the pathogenesis of experimental hematogenously disseminated candidiasis. This work will optimize a vaccine based on candidal adhesins and determine the effects of immune serum on adherence to host tissue. Project 4 will investigate the molecular mechanisms by which C. albicans activates the complement system, leading to deposition of C3 fragments on the fungal surface. The influence of the fungal surface on the mechanism(s) for initiation, amplification and regulation of the complement system will be evaluated. The importance and contributions of C3 to adhesion of C. albicans will be evaluated by the other members of the Research Unit using in vitro and in vivo systems. Project 5 will isolate genes encoding cell surface proteins by functional complementation of a secretory-defective reporter gene. Those genes regulated in response to environmental signals known to alter the candidal cell surface will be identified by differential hybridization screening. The structure and function of this subset of genes will be explored by a combination of genetic and biochemical approaches.
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