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

白色念珠菌是一种在大多数健康人的胃肠道中无害的共生菌，也是人类最重要的真菌病原体之一，尤其是在免疫功能低下的患者中。白念珠菌可以通过产生基因改变的变种来适应在其人类宿主中遇到的新挑战。一个具有高度临床重要性的例子是对广泛使用的抗真菌药物氟康唑产生抗药性，氟康唑抑制麦角固醇的生物合成。药物靶向酶的突变和转录因子的功能获得突变导致麦角固醇生物合成基因的过度表达和多药外排泵，所有这些都增加了对氟康唑的耐药性。许多临床分离的白色念珠菌表现出其中的几种机制，因此获得了高水平的耐药性。此外，基因组重排经常导致突变等位基因的纯合性，并进一步提高耐药性。这种基因组改变在胁迫条件下频率增加，可能会影响多条染色体，并伴随着交配型基因座杂合性的丧失。后者允许细胞切换到一种新的、具有交配能力的形态，这表明耐药细胞已经获得了通过有性重组交换耐药基因的能力。携带高活性转录因子的菌株中基因表达的放松也导致了在没有药物的情况下的适应性缺陷。然而，临床分离的白色念珠菌可能通过未知的机制克服耐药的适应成本。在这个项目中，我们将探索交配和性重组是否有助于在最初克隆的药物敏感细胞群体中产生高度耐药的变异。此外，我们将研究耐氟康唑的白色念珠菌菌株通过哪些机制可以在不丧失耐药性的情况下重新获得更好的适应能力。这些研究将为白念珠菌在与人类宿主的终身联系过程中不断适应环境变化的机制提供洞察力。

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.