Comparative Genomics of Serial Isolates of Cryptococcus neoformans Reveals Gene Associated With Carbon Utilization and Virulence.
Comparative Genomics of Serial Isolates of Cryptococcus neoformans Reveals Gene Associated With Carbon Utilization and Virulence.
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DOI：
10.1534/g3.113.005660
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发表时间：
2013-04-09
期刊：
影响因子：
--
通讯作者：
Fraser JA
中科院分区：
文献类型：
--
作者：
Ormerod KL;Morrow CA;Chow EW;Lee IR;Arras SD;Schirra HJ;Cox GM;Fries BC;Fraser JA
机会性真菌病原体新生隐球菌是人类免疫缺陷病毒/获得性免疫缺陷综合征人群死亡的主要原因，并以经常导致危及生命的复发而闻名。为了研究宿主内微进化对持续和复发的潜在贡献，我们分析了从一名患有艾滋病的患者身上获得的两种系列分离株，该患者患有首发和复发的隐球菌性脑膜脑炎。尽管这些分离株在多位点序列分型方面是相同的，但它们的表型不同，表现出关键毒力因子、营养获取、代谢谱以及在动物模型中传播能力的变化。全基因组测序揭示了一种克隆关系，只有少数独特的差异。其中，两个关键的变化有望解释在复发分离株中观察到的表型差异：一个预测的富含AT相互作用结构域蛋白的丢失和12号染色体左、右臂拷贝数的变化。预测的转录调节基因的缺失导致黑色素、被膜、碳源的使用和在宿主中的扩散的变化，这与复发分离株的表型一致。此外，缺失突变体在小鼠模型中显示出改变的毒力。观察到的差异表明，复发分离株是在侵入中枢神经系统后进化的，可能在给予抗真菌治疗后获得了优势。这些数据揭示了对新生隐球菌基因组在人类感染期间如何变化以及这种致命真菌病原体的微进化进展方式的第一次分子洞察。
The opportunistic fungal pathogen Cryptococcus neoformans is a leading cause of mortality among the human immunodeficiency virus/acquired immunodeficiency syndrome population and is known for frequently causing life-threatening relapses. To investigate the potential contribution of in-host microevolution to persistence and relapse, we have analyzed two serial isolates obtained from a patient with acquired immunodeficiency syndrome who suffered an initial and relapse episode of cryptococcal meningoencephalitis. Despite being identical by multilocus sequence typing, the isolates differ phenotypically, exhibiting changes in key virulence factors, nutrient acquisition, metabolic profiles, and the ability to disseminate in an animal model. Whole-genome sequencing uncovered a clonal relationship, with only a few unique differences. Of these, two key changes are expected to explain the phenotypic differences observed in the relapse isolate: loss of a predicted AT-rich interaction domain protein and changes in copy number of the left and right arms of chromosome 12. Gene deletion of the predicted transcriptional regulator produced changes in melanin, capsule, carbon source use, and dissemination in the host, consistent with the phenotype of the relapse isolate. In addition, the deletion mutant displayed altered virulence in the murine model. The observed differences suggest the relapse isolate evolved subsequent to penetration of the central nervous system and may have gained dominance following the administration of antifungal therapy. These data reveal the first molecular insights into how the Cryptococcus neoformans genome changes during infection of humans and the manner in which microevolution progresses in this deadly fungal pathogen.
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影响因子：
6.4
作者：
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