TOR1 dysfunction promotes phenotypic diversity in the asexual fungusCandida albicans

Abstract

AbstractGenetic variation is a primary contributor to phenotypic variation within a population. However, it is unclear how, or if, genetic variation is generated and maintained to promote phenotypic variation in asexual eukaryotes.C. albicans, an asexual fungus that causes opportunistic infections in susceptible hosts, has several phenotypic switching systems, including the colony morphology phenotypic switching (CMPS) system. CMPS, a penetrant change in colony morphology on solid mediumin vitro, is associated with incipient or fulminant clinical disease. CMPS results in the alteration of additional virulence properties, such as drug resistance and protease secretion, that are not tightly correlated with colony morphology. Importantly, it is unknown whether CMPS is a regulated or stochastic process. We found that specific mutants affecting theTargetofRapamycin (TOR) pathway showed an increase in CMPS frequency and CMPS in these mutant backgrounds was associated with changes in rapamycin sensitivity. We also identified growth conditions that promoted CMPS in clinical strains and found that CMPS in these backgrounds was also linked to the TOR pathway through changes in rapamycin sensitivity. These results demonstrate that CMPS promotes phenotypic variation through the TOR pathway, supporting a model that this is a regulated process. Since the TOR growth control pathway is conserved throughout the eukarya, the identification of TOR as a phenotypic diversity regulator likely has broad implications.