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

表型转换和基因组改变作为机会性真菌病原体白色念珠菌的宿主适应机制

基本信息

批准号：
170788626
负责人：
Professor Dr. Joachim Morschhäuser
金额：
--
依托单位：
Institut für Molekulare Infektionsbiologie (IMIB)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/170788626?language=en
关键词：
Phenotypic switching genomic alterations host

项目摘要

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.

白色念珠菌是大多数健康人胃肠道中的一种无害真菌，但也是人类最重要的真菌病原体之一，特别是在免疫功能低下的患者中。C.白色念珠菌可以通过产生基因改变的变体来适应在其人类宿主中遇到的新挑战。具有高度临床重要性的一个例子是对广泛使用的抗真菌药物氟康唑的耐药性的发展，氟康唑抑制麦角固醇的生物合成。药物靶酶突变和转录因子功能获得性突变导致麦角固醇生物合成基因和多药外排泵的过度表达，所有这些都增加了氟康唑耐药性。许多临床C。白色念珠菌分离株表现出这些机制中的几种，从而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和进一步提高的耐药性。这种基因组改变在应激条件下频率增加，可能影响多条染色体，并伴随着交配型基因座杂合性的丢失。后一个事件允许细胞切换到一个新的，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。携带过度活跃的转录因子的菌株中的基因表达失调也会在不存在药物的情况下导致适应性缺陷。然而，临床C。白色念珠菌分离株可能通过未知的机制克服耐药性的适应性成本。在这个项目中，我们将探索交配和有性重组是否有助于在药物敏感细胞的原始克隆群体中产生高度耐药的变异体。此外，我们还将研究氟康唑耐药的C。白色念珠菌菌株可以重新获得增加的适应性而不丧失耐药性。这些研究将提供深入了解的机制，使C。白念珠菌在与人类宿主的终身关系中不断适应环境的变化。