Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA.
Antimicrob Agents Chemother. 2013 Oct;57(10):5026-36. doi: 10.1128/AAC.00516-13. Epub 2013 Jul 29.
Candida albicans is a prevailing fungal pathogen with a diploid genome that can adapt to environmental stresses by losing or gaining an entire chromosome or a large portion of a chromosome. We have previously found that the loss of one copy of chromosome 5 (Ch5) allows for adaptation to the toxic sugar l-sorbose. l-Sorbose is similar to caspofungin and other antifungals from the echinocandins class, in that it represses synthesis of cell wall glucan in fungi. Here, we extended the study of the phenotypes controlled by Ch5 copy number. We examined 57 strains, either disomic or monosomic for Ch5 and representing five different genetic backgrounds, and found that the monosomy of Ch5 causes elevated levels of chitin and repressed levels of 1,3-β-glucan components of the cell wall, as well as diminished cellular ergosterol. Increased deposition of chitin in the cell wall could be explained, at least partially, by a 2-fold downregulation of CHT2 on the monosomic Ch5 that encodes chitinase and a 1.5-fold upregulation of CHS7 on Ch1 that encodes the protein required for wild-type chitin synthase III activity. Other important outcomes of Ch5 monosomy consist of susceptibility changes to agents representing four major classes of antifungals. Susceptibility to caspofungin increased or decreased and susceptibility to 5-fluorocytosine decreased, whereas susceptibility to fluconazole and amphotericin B increased. Our results suggest that Ch5 monosomy represents an unrecognized C. albicans regulatory strategy that impinges on multiple stress response pathways.
白色念珠菌是一种流行的真菌病原体，具有二倍体基因组，可通过丢失或获得整条染色体或染色体的大部分来适应环境压力。我们之前发现，丢失一条染色体 5（Ch5）可以使酵母适应有毒的 L-山梨糖。L-山梨糖与棘白菌素和其他来自棘白菌素类的抗真菌药物相似，因为它抑制真菌细胞壁葡聚糖的合成。在这里，我们扩展了对 Ch5 拷贝数控制的表型的研究。我们检查了 57 株单倍体或二倍体的 Ch5 菌株，它们代表五个不同的遗传背景，发现 Ch5 的单倍体导致细胞壁几丁质水平升高，1,3-β-葡聚糖成分水平降低，以及细胞麦角固醇减少。细胞壁中几丁质的沉积增加至少可以部分解释为编码几丁质酶的 CHT2 在单倍体 Ch5 上的 2 倍下调，以及编码野生型几丁质合酶 III 活性所需蛋白的 CHS7 在 Ch1 上的 1.5 倍上调。Ch5 单倍体的其他重要结果包括对代表四种主要类别的抗真菌药物的敏感性变化。对卡泊芬净的敏感性增加或降低，对 5-氟胞嘧啶的敏感性降低，而对氟康唑和两性霉素 B 的敏感性增加。我们的结果表明，Ch5 单倍体代表了一种未被识别的白色念珠菌调控策略，该策略影响多个应激反应途径。
