Systemic Approach to Virulence Gene Network Analysis for Gaining New Insight into Cryptococcal Virulence.
Systemic Approach to Virulence Gene Network Analysis for Gaining New Insight into Cryptococcal Virulence.
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DOI：
10.3389/fmicb.2016.01652
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发表时间：
2016
影响因子：
5.2
通讯作者：
Olszewski MA
中科院分区：
文献类型：
--
作者：
Malachowski AN;Yosri M;Park G;Bahn YS;He Y;Olszewski MA
新型隐球菌是一种致病性酵母菌，在全球范围内对感染患者造成高度致命的感染。新生梭状菌通常会在哺乳动物肺组织中引发感染，随后扩散到中枢神经系统，在那里引起严重的病理。新形态芽孢杆菌的毒力基因正以越来越快的速度被表征，然而，我们对它们的作用和遗传相互作用还远远没有全面的了解。其中一些报道的毒性基因分散在不同的数据库中，而另一些尚未包括在内。本研究收集并分析了150例报道的新生弧菌毒力相关因子（VAFs）。利用网络资源STRING数据库，我们的研究确定了总VAFs与专门参与肺部和大脑感染的VAFs之间的不同相互作用，并确定了一个新的菌株特异性毒力基因SHO1，该基因参与有丝分裂原激活的蛋白激酶信号通路。正如我们的分析所预测的那样，在肺部感染的小鼠模型中，SHO1表达增强了新生梭状菌的毒力，促进了非保护性免疫Th2偏倚的增强，并逐渐增强了感染肺部的真菌生长。序列分析表明，77.4%（116个）的VAFs为可溶性蛋白，22.7%（34个）为跨膜蛋白。在隐球菌VAFs中，蛋白激酶和转录因子等参与调控和信号传导的基序高度富集。总的来说，这项研究代表了使用系统生物学方法分析新形态c的毒力复合网络的开创性努力。
Cryptococcus neoformans is pathogenic yeast, responsible for highly lethal infections in compromised patients around the globe. C. neoformans typically initiates infections in mammalian lung tissue and subsequently disseminates to the central nervous system where it causes significant pathologies. Virulence genes of C. neoformans are being characterized at an increasing rate, however, we are far from a comprehensive understanding of their roles and genetic interactions. Some of these reported virulence genes are scattered throughout different databases, while others are not yet included. This study gathered and analyzed 150 reported virulence associated factors (VAFs) of C. neoformans. Using the web resource STRING database, our study identified different interactions between the total VAFs and those involved specifically in lung and brain infections and identified a new strain specific virulence gene, SHO1, involved in the mitogen-activated protein kinase signaling pathway. As predicted by our analysis, SHO1 expression enhanced C. neoformans virulence in a mouse model of pulmonary infection, contributing to enhanced non-protective immune Th2 bias and progressively enhancing fungal growth in the infected lungs. Sequence analysis indicated 77.4% (116) of total studied VAFs are soluble proteins, and 22.7% (34) are transmembrane proteins. Motifs involved in regulation and signaling such as protein kinases and transcription factors are highly enriched in Cryptococcus VAFs. Altogether, this study represents a pioneering effort in analysis of the virulence composite network of C. neoformans using a systems biology approach.