Comparative genomic and transcriptomic analyses unveil novel features of azole resistance and adaptation to the human host in Candida glabrata
Comparative genomic and transcriptomic analyses unveil novel features of azole resistance and adaptation to the human host in Candida glabrata
复制标题
比较基因组和转录组分析揭示了光滑念珠菌对唑类抗性和对人类宿主的适应的新特征
DOI：
10.1093/femsyr/fox079
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发表时间：
2018
影响因子：
3.2
通讯作者：
Mira N.
中科院分区：
文献类型：
--
作者：
Salazar S;Wang C;Munsterkotter M;Okamoto M;Takahashi-Nakaguchi A;Chibana H;Lopes M;Guldener U;Butler G;Mira N.
对唑类药物耐药的光滑念珠菌菌株的频繁出现增加了该菌种引起的感染的发生率。氟康唑和伏立康唑耐药临床分离株（FFUL 887）的全基因组测序和随后与敏感菌株CBS 138的基因组比较显示，在C中记录的促进唑类耐药的几个基因存在显著差异。光滑的其中包括转录调节因子CgPdr 1。CgPdr 1 FFUL 887等位基因包括K274 Q修饰，在其他唑类耐药菌株中没有记录。转录组学分析证明了FFUL 887菌株中92个记录的CgPdr 1靶点的上调，支持K274 Q取代起源于CgPdr 1功能获得性突变体的观点。在FFUL 887背景下CgPDR 1 K274的表达使细胞在低pH（4.5）下对高浓度有机酸敏感，但对其他环境应激物的耐受性没有可检测的影响。FFUL 887和CBS 138的基因组的比较也揭示了粘附素编码基因序列的显著差异，而两种菌株的转录组的比较显示了FFUL 887菌株中参与碳水化合物、氮和硫代谢的基因表达的显著重塑;这些反应可能反映了在宿主定殖期间由临床菌株进化的适应性反应。
The frequent emergence of azole resistance amongCandida glabratastrains contributes to increase the incidence of infections caused by this species. Whole-genome sequencing of a fluconazole and voriconazole-resistant clinical isolate (FFUL887) and subsequent comparison with the genome of the susceptible strain CBS138 revealed prominent differences in several genes documented to promote azole resistance inC. glabrata. Among these was the transcriptional regulator CgPdr1. The CgPdr1 FFUL887 allele included a K274Q modification not documented in other azole-resistant strains. Transcriptomic profiling evidenced the upregulation of 92 documented targets of CgPdr1 in the FFUL887 strain, supporting the idea that the K274Q substitution originates a CgPdr1 gain-of-function mutant. The expression ofCgPDR1K274Qin the FFUL887 background sensitised the cells against high concentrations of organic acids at a low pH (4.5), but had no detectable effect in tolerance towards other environmental stressors. Comparison of the genome of FFUL887 and CBS138 also revealed prominent differences in the sequence of adhesin-encoding genes, while comparison of the transcriptome of the two strains showed a significant remodelling of the expression of genes involved in metabolism of carbohydrates, nitrogen and sulphur in the FFUL887 strain; these responses likely reflecting adaptive responses evolved by the clinical strain during colonisation of the host.