The dimorphic yeast Candida albicans is capable of growing in either a budding or hyphal form. Although it has been assumed that its pathogenicity depends to a large extent upon its dimorphism, this single developmental characteristic has never seemed to be sufficient to account for its pathogenic success. Recently, we discovered that a standard laboratory strain of C. albicans switches heritably and at high frequency 10-2 between a number of specific general phenotypes identified by colony morphology on agar. These phenotypes include """"""""star"""""""", """"""""ring"""""""", """"""""irregular wrinkle"""""""", """"""""hat"""""""", """"""""stipple"""""""" and """"""""fuzzy"""""""". In addition, we have discovered a second switching phenomenon in which strains switch back and forth between a white and opaque colony at frequences of roughly 10-2 to 10-3. Cells in the white form are indistinguishable from cells of the standard strains of C. albicans, but cells in the opaque form are morphologically distinct and incapable of forming hyphae. In this proposal, we have outlined a set of experiments 1) to complete the characterization of high frequency switching of colony morphology in the standard laboratory strain 3153A as well as in a number of commensals and pathogenic isolates, 2) to examine in detail the changes in environmental constraints on the bud to hypha transition which accompany switching, 3) to assess the changes in budding pattern, zones of cell wall expansion, chitin deposition, and dynamics of actin, tubulin and intermediate filament protein localization which may accompany switching, 4) to complete the characterization of high frequency switching between white and opaque colony formation, 5) to analyze the differences in budding pattern, wall expansion and cytoskeleton between white and opaque cells, 6) to identify antigenic differences between the switch phenotypes by antisera and by 2D-PAGE analysis of pulse-labeled polypeptides, 7) to continue to analyze the genome for transpositions which may be basic to the switching processes, 8) to clone genes differentially expressed in the different switch phenotypes and 9) to complete our analysis of antibiotic resistance associated with switching. These newly discovered switching processes may be due to mobile genetic elements and may afford C. albicans and related pathogens with the capacity to 1) invade different body locations, 2) evade antibiotic treatment, 3) evade the immune system, and 4) respond to different physiological cues.
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