Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling
Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling
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DOI：
10.1128/aac.00071-17
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发表时间：
2017-05-01
影响因子：
4.9
通讯作者：
Rustchenko, Elena
中科院分区：
文献类型：
--
作者：
Yang, Feng;Zhang, Lulu;Rustchenko, Elena
扩大棘球菌素用于预防或治疗侵袭性真菌感染的范围，导致由于耐药念珠菌物种而导致的突破性感染数量增加。尽管不常见，但白念珠菌对棘球菌素耐药的情况有很好的记录，白念珠菌是最常见的血液微生物之一。需要更好的理解来评估促进耐受性的细胞因素，并使感染细胞在临床上取得突破。我们之前的研究表明，一些由于丢失一条5号染色体(CH5)而适应在有毒山梨糖存在的情况下生长的突变体也变得对卡泊芬净更耐受。我们发现，在卡泊芬净上直接选择突变体后，至少有三种机制可以授予耐受性：(I)CH5的单体，(Ii)CH5的左臂单体和右臂三体的组合，以及(Iii)非整倍体独立的机制。耐受性突变体的细胞壁甲壳素水平升高，细胞壁生物合成相关基因FKS和CHT2表达下调，与CH5倍体无关。与CH5倍体无关，参与钙调神经磷酸酶信号通路的CH5上的CNB1和MID1基因在二倍体水平表达。因此，多种机制可以影响上述基因的相对表达，以类似的方式控制它们。尽管FKS1两个特定区域的突破性突变以前与卡泊芬净耐药有关，但我们发现卡泊芬净耐药机制独立于FKS1，因此代表了耐药性发展的早期事件。
Expanding echinocandin use to prevent or treat invasive fungal infections has led to an increase in the number of breakthrough infections due to resistant Candida species. Although it is uncommon, echinocandin resistance is well documented for Candida albicans, which is among the most prevalent bloodstream organisms. A better understanding is needed to assess the cellular factors that promote tolerance and predispose infecting cells to clinical breakthrough. We previously showed that some mutants that were adapted to growth in the presence of toxic sorbose due to loss of one chromosome 5 (Ch5) also became more tolerant to caspofungin. We found here, following direct selection of mutants on caspofungin, that tolerance can be conferred by at least three mechanisms: (i) monosomy of Ch5, (ii) combined monosomy of the left arm and trisomy of the right arm of Ch5, and (iii) an aneuploidy-independent mechanism. Tolerant mutants possessed cell walls with elevated chitin and showed downregulation of genes involved in cell wall biosynthesis, namely, FKS, located outside Ch5, and CHT2, located on Ch5, irrespective of Ch5 ploidy. Also irrespective of Ch5 ploidy, the CNB1 and MID1 genes on Ch5, which are involved in the calcineurin signaling pathway, were expressed at the diploid level. Thus, multiple mechanisms can affect the relative expression of the aforementioned genes, controlling them in similar ways. Although breakthrough mutations in two specific regions of FKS1 have previously been associated with caspofungin resistance, we found mechanisms of caspofungin tolerance that are independent of FKS1 and thus represent an earlier event in resistance development.