Phenotypic switching and genomic alterations as host adaptation mechanisms of the opportunistic fungal pathogen Candida albicans

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The yeast Candida albicans is a harmless commensal in the gastrointestinal tract of most healthy people, but also one of the most important fungal pathogens of humans, especially in immunocompromised patients. C. albicans can adapt to new challenges encountered in its human host by the generation of genetically altered variants. An example of high clinical importance is the development of resistance to the widely used antifungal drug fluconazole, which inhibits ergosterol biosynthesis. Mutations in the drug target enzyme and gain-of-function mutations in transcription factors, which result in the overexpression of ergosterol biosynthesis genes and multidrug efflux pumps, all confer increased fluconazole resistance. Many clinical C.¿albicans isolates exhibit several of these mechanisms and thereby have acquired high levels of drug resistance. In addition, genome rearrangements frequently lead to homozygosity for the mutated alleles and further elevated drug resistance. Such genomic alterations, which increase in frequency under stress conditions, may affect multiple chromosomes and be accompanied by loss of heterozygosity at the mating type locus. The latter event allows the cells to switch to a new, mating-competent morphology, suggesting that drug-resistant cells have acquired the ability to exchange resistance genes by sexual recombination. The deregulated gene expression in strains carrying hyperactive transcription factors also causes a fitness defect in the absence of the drug. However, clinical C.¿albicans isolates may overcome the fitness costs of drug resistance by unknown mechanisms. In this project, we will explore if mating and sexual recombination contribute to the generation of highly resistant variants within an originally clonal population of drug-susceptible cells. Furthermore, we will investigate by which mechanisms fluconazole-resistant C. albicans strains can regain increased fitness without losing drug resistance. These studies will provide insight into the mechanisms that enable C. albicans to continuously adapt to alterations in its environment during the lifelong association with its human host.