Evolution of Fluconazole-Resistant Candida albicans Strains by Drug-Induced Mating Competence and Parasexual Recombination
Evolution of Fluconazole-Resistant Candida albicans Strains by Drug-Induced Mating Competence and Parasexual Recombination
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DOI：
10.1128/mbio.02740-18
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发表时间：
2019-01-01
期刊：
影响因子：
6.4
通讯作者：
Morschhaeuser, Joachim
中科院分区：
文献类型：
--
作者：
Popp, Christina;Ramirez-Zavala, Bernardo;Morschhaeuser, Joachim
白色念珠菌的克隆群体结构表明，（准）有性重组在这种机会性真菌病原体的生活方式中并不发挥重要作用，大多数白色念珠菌菌株在交配型基因座（MTL）处是杂合的，因此交配无能，这一事实强化了这一假设。另一方面，交配可能发生在克隆群体内，并允许单个细胞获得的有利特征组合以适应不利条件。我们研究了准性重组是否可能参与对氟康唑（一种常用于治疗白色念珠菌感染的抗真菌药物）表现出多种耐药机制的高度耐药菌株的进化。在药物存在下，MTL 杂合菌株和不同氟康唑耐药突变的生长导致了突变等位基因和交配型基因座纯合的衍生物的出现，并表现出耐药性增加。当这些品系的 MTLa/a 和 MTL α/α 细胞以所有可能的组合混合时，我们可以分离出含有父母双方遗传物质的交配产物。最初的交配产物并未表现出比亲本菌株更高的耐药性，但在选择压力下的进一步繁殖导致野生型等位基因的丧失和氟康唑耐药性的增加。因此，氟康唑治疗不仅选择耐药突变，而且促进赋予交配能力的基因组改变，使原始克隆群体中的细胞能够交换各自获得的耐药机制并产生高度耐药的后代。 重要性 有性生殖是物种进化的重要机制，因为它允许群体中个体成员的有利性状组合。致病性酵母白色念珠菌是一种二倍体生物，通常以克隆方式繁殖，因为交配型基因座 (MTL) 的杂合性会抑制细胞之间的交配。在这里，我们表明，在用常用抗真菌剂氟康唑治疗期间获得耐药性突变的白色念珠菌细胞，通过基因组重排迅速产生进一步增强的耐药性，导致突变等位基因和交配型基因座的杂合性同时丧失。这使得群体中的耐药细胞能够转变为具有交配能力的不透明形态，并相互交配以结合不同的个体获得性耐药机制。四倍体交配产物重新排列其合并的基因组，并在药物的选择压力下产生高度抗性的后代，保留了有利的突变等位基因。因此，由应激诱导的基因组重排促进的准有性繁殖，导致具有适应性突变的细胞获得交配能力，因此可能是白色念珠菌种群进化的重要机制。
The clonal population structure of Candida albicans suggests that (para)sexual recombination does not play an important role in the lifestyle of this opportunistic fungal pathogen, an assumption that is strengthened by the fact that most C. albicans strains are heterozygous at the mating type locus (MTL) and therefore mating-incompetent. On the other hand, mating might occur within clonal populations and allow the combination of advantageous traits that were acquired by individual cells to adapt to adverse conditions. We have investigated if parasexual recombination may be involved in the evolution of highly drug-resistant strains exhibiting multiple resistance mechanisms against fluconazole, an antifungal drug that is commonly used to treat infections by C. albicans. Growth of strains that were heterozygous for MTL and different fluconazole resistance mutations in the presence of the drug resulted in the emergence of derivatives that had become homozygous for the mutated allele and the mating type locus and exhibited increased drug resistance. When MTLa/a and MTL alpha/alpha cells of these strains were mixed in all possible combinations, we could isolate mating products containing the genetic material from both parents. The initial mating products did not exhibit higher drug resistance than their parental strains, but further propagation under selective pressure resulted in the loss of the wild-type alleles and increased fluconazole resistance. Therefore, fluconazole treatment not only selects for resistance mutations but also promotes genomic alterations that confer mating competence, which allows cells in an originally clonal population to exchange individually acquired resistance mechanisms and generate highly drug-resistant progeny.IMPORTANCE Sexual reproduction is an important mechanism in the evolution of species, since it allows the combination of advantageous traits of individual members in a population. The pathogenic yeast Candida albicans is a diploid organism that normally propagates in a clonal fashion, because heterozygosity at the mating type locus (MTL) inhibits mating between cells. Here we show that C. albicans cells that have acquired drug resistance mutations during treatment with the commonly used antifungal agent fluconazole rapidly develop further increased resistance by genome rearrangements that result in simultaneous loss of heterozygosity for the mutated allele and the mating type locus. This enables the drug-resistant cells of a population to switch to the mating-competent opaque morphology and mate with each other to combine different individually acquired resistance mechanisms. The tetraploid mating products reassort their merged genomes and, under selective pressure by the drug, generate highly resistant progeny that have retained the advantageous mutated alleles. Parasexual propagation, promoted by stress-induced genome rearrangements that result in the acquisition of mating competence in cells with adaptive mutations, may therefore be an important mechanism in the evolution of C. albicans populations.