Global transcriptome profile of Cryptococcus neoformans during exposure to hydrogen peroxide induced oxidative stress.
Global transcriptome profile of Cryptococcus neoformans during exposure to hydrogen peroxide induced oxidative stress.
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DOI：
10.1371/journal.pone.0055110
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lodge JK
中科院分区：
文献类型：
--
作者：
Upadhya R;Campbell LT;Donlin MJ;Aurora R;Lodge JK
机会性真菌病原体新型隐球菌抵抗氧化应激的能力是其最重要的毒力相关特征之一。为了应对巨噬细胞内部氧化爆发引起的细胞损伤的有害影响，新型隐球菌已经发展出多层冗余分子反应来中和应激、修复损伤并最终在吞噬体的恶劣环境中生长。我们对在营养成分确定的培养基中多个时间点用过氧化氢 (H2O2) 处理的细胞进行微阵列分析，以确定与氧化应激相关的转录特征。我们发现真菌细胞生长和处理的培养基成分对其降解外源 H2O2 的能力具有深远的影响。我们通过在不同条件下生长酵母细胞来确定 H2O2 分解的动力学，并相应地选择合适的培养基成分和时间点范围来分离 RNA 进行杂交。微阵列分析揭示了强大的瞬时转录反应，并且整体反应的强度与处理细胞分解 H2O2 的动力学一致。对与氧化还原、代谢过程和蛋白质分解代谢过程相关的差异表达基因进行基因本体分析，确定了线粒体功能和蛋白质泛素化在氧化应激抵抗中的潜在作用。有趣的是，新型隐球菌对 H2O2 处理的代谢途径适应与其他真菌生物体对氧化应激的反应明显不同。我们还发现用 H2O2 处理新生隐球菌后会诱导抗真菌药物耐药性反应。这些结果凸显了氧化应激反应的复杂性，并为提高我们对新型隐球菌氧化应激抵抗机制的理解提供了可能的新途径。
The ability of the opportunistic fungal pathogen Cryptococcus neoformans to resist oxidative stress is one of its most important virulence related traits. To cope with the deleterious effect of cellular damage caused by the oxidative burst inside the macrophages, C. neoformans has developed multilayered redundant molecular responses to neutralize the stress, to repair the damage and to eventually grow inside the hostile environment of the phagosome. We used microarray analysis of cells treated with hydrogen peroxide (H2O2) at multiple time points in a nutrient defined medium to identify a transcriptional signature associated with oxidative stress. We discovered that the composition of the medium in which fungal cells were grown and treated had a profound effect on their capacity to degrade exogenous H2O2. We determined the kinetics of H2O2 breakdown by growing yeast cells under different conditions and accordingly selected an appropriate media composition and range of time points for isolating RNA for hybridization. Microarray analysis revealed a robust transient transcriptional response and the intensity of the global response was consistent with the kinetics of H2O2 breakdown by treated cells. Gene ontology analysis of differentially expressed genes related to oxidation-reduction, metabolic process and protein catabolic processes identified potential roles of mitochondrial function and protein ubiquitination in oxidative stress resistance. Interestingly, the metabolic pathway adaptation of C. neoformans to H2O2 treatment was remarkably distinct from the response of other fungal organisms to oxidative stress. We also identified the induction of an antifungal drug resistance response upon the treatment of C. neoformans with H2O2. These results highlight the complexity of the oxidative stress response and offer possible new avenues for improving our understanding of mechanisms of oxidative stress resistance in C. neoformans.
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