Network Modeling Reveals Cross Talk of MAP Kinases during Adaptation to Caspofungin Stress in Aspergillus fumigatus.
Network Modeling Reveals Cross Talk of MAP Kinases during Adaptation to Caspofungin Stress in Aspergillus fumigatus.
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DOI：
10.1371/journal.pone.0136932
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Valiante V
中科院分区：
文献类型：
--
作者：
Altwasser R;Baldin C;Weber J;Guthke R;Kniemeyer O;Brakhage AA;Linde J;Valiante V
丝裂原活化蛋白激酶（MAPK）在真核生物中高度保守。在病原真菌中，它们的活性被分配给不同的生理功能，包括药物适应和抗性。烟曲霉是一种人类致病真菌，可引起危及生命的侵袭性感染。针对侵袭性真菌病的治疗选择仍然有限。临床上使用的药物之一是卡泊芬净，其特异性靶向真菌细胞壁生物合成。基于全面的转录组数据集和数学建模，采用系统生物学方法来推断调节网络，并确定A.烟熏。数学建模和实验验证证实了细胞壁完整性和高渗透压甘油信号通路之间发生的密切串扰。具体而言，增加浓度的卡泊芬净促进这些信号的激活。此外，卡泊芬净影响细胞内转运，这引起了额外的渗透压，这是独立的葡聚糖抑制。高浓度的卡泊芬净减少这种渗透胁迫，从而降低其毒性活性。我们的研究结果表明，MAPK信号通路在卡泊芬净适应过程中起着关键作用，并有助于这种药物产生的矛盾效应。
Mitogen activated protein kinases (MAPKs) are highly conserved in eukaryotic organisms. In pathogenic fungi, their activities were assigned to different physiological functions including drug adaptation and resistance. Aspergillus fumigatus is a human pathogenic fungus, which causes life-threatening invasive infections. Therapeutic options against invasive mycoses are still limited. One of the clinically used drugs is caspofungin, which specifically targets the fungal cell wall biosynthesis. A systems biology approach, based on comprehensive transcriptome data sets and mathematical modeling, was employed to infer a regulatory network and identify key interactions during adaptation to caspofungin stress in A. fumigatus. Mathematical modeling and experimental validations confirmed an intimate cross talk occurring between the cell wall-integrity and the high osmolarity-glycerol signaling pathways. Specifically, increased concentrations of caspofungin promoted activation of these signalings. Moreover, caspofungin affected the intracellular transport, which caused an additional osmotic stress that is independent of glucan inhibition. High concentrations of caspofungin reduced this osmotic stress, and thus decreased its toxic activity. Our results demonstrated that MAPK signaling pathways play a key role during caspofungin adaptation and are contributing to the paradoxical effect exerted by this drug.