Phenotypic Switching inCandida glabrataAccompanied by Changes in Expression of Genes with Deduced Functions in Copper Detoxification and Stress

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Abstract
Most strains of Candida glabrata switch spontaneously between a number of phenotypes distinguishable by graded brown coloration on agar containing 1 mM CuSO4, a phenomenon referred to as “core switching.” C. glabrata also switches spontaneously and reversibly from core phenotypes to an irregular wrinkle (IWr) phenotype, a phenomenon referred to as “irregular wrinkle switching.” To identify genes differentially expressed in the core phenotypes white (Wh) and dark brown (DB), a cDNA subtraction strategy was employed. Twenty-three genes were identified as up-regulated in DB, four in Wh, and six in IWr. Up-regulation was verified in two unrelated strains, one a and one α strain. The functions of these genes were deduced from the functions of their Saccharomyces cerevisiae orthologs. The majority of genes up-regulated in DB (78%) played deduced roles in copper assimilation, sulfur assimilation, and stress responses. These genes were differentially up-regulated in DB even though the conditions of growth for Wh and DB, including CuSO4 concentration, were identical. Hence, the regulation of these genes, normally regulated by environmental cues, has been usurped by switching, presumably as an adaptation to the challenging host environment. These results are consistent with the suggestion that switching provides colonizing populations with a minority of cells expressing a phenotype that allows them to enrich in response to an environmental challenge, a form of rapid adaptation. However, DB is the most commonly expressed phenotype at sites of host colonization, in the apparent absence of elevated copper levels. Hence, up-regulation of these genes by switching suggests that in some cases they may play roles in colonization and virulence not immediately obvious from the roles played by their orthologs in S. cerevisiae.