Activation and Alliance of Regulatory Pathways in C. albicans during Mammalian Infection
Activation and Alliance of Regulatory Pathways in C. albicans during Mammalian Infection
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DOI：
10.1371/journal.pbio.1002076
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发表时间：
2015-02-01
期刊：
影响因子：
9.8
通讯作者：
Mitchell, Aaron P.
中科院分区：
文献类型：
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作者：
Xu, Wenjie;Solis, Norma V.;Mitchell, Aaron P.
基因表达动力学提供了对几乎所有生物过程的基础性见解。在这里，我们分析环境响应基因和转录因子基因的表达，以推断在白念珠菌侵袭哺乳动物宿主的过程中驱动病原体基因调控的信号和途径。环境响应性基因的表达表明，感染有早期和晚期。早期阶段包括锌和铁限制基因的诱导，对转录因子Rim101反应的基因，以及侵袭性菌丝细胞的特征基因。晚期包括与巨噬细胞吞噬有关的反应。转录因子基因的表达也反映了早期和晚期。体内毒力或增殖所需的转录因子基因在高表达的转录因子基因中富含。在感染过程中，有6个转录因子基因缺陷的突变株，其中3个以前被详细研究过(Rim101，Efg1，Zap1)，3个较少被研究(Rob1，Rpn4，Sut1)。与体外生长相比，这些突变体中的大多数在感染期间具有不同的基因表达谱。感染图谱表明Sut1与Zap1的作用途径相同，我们证实了ZAP1或Zap1依赖的锌转运蛋白基因ZRT2的过表达可以恢复对sut1突变体的致病性这一功能关系。细胞壁抑制剂卡泊芬净的干扰也对体内和体外的基因表达产生了明显的影响。出乎意料的是，卡泊芬净诱导了许多在感染早期被抑制的相同基因，我们认为这一现象可能有助于药物疗效。病原体反应电路在感染期间是独特的，与许多相关的调控关系在体外生长过程中并不明显。我们的发现支持这样的原理，即毒力是一种仅在宿主-病原体相互作用发生的不同环境中表现出来的特性。
Gene expression dynamics have provided foundational insight into almost all biological processes. Here, we analyze expression of environmentally responsive genes and transcription factor genes to infer signals and pathways that drive pathogen gene regulation during invasive Candida albicans infection of a mammalian host. Environmentally responsive gene expression shows that there are early and late phases of infection. The early phase includes induction of zinc and iron limitation genes, genes that respond to transcription factor Rim101, and genes characteristic of invasive hyphal cells. The late phase includes responses related to phagocytosis by macrophages. Transcription factor gene expression also reflects early and late phases. Transcription factor genes that are required for virulence or proliferation in vivo are enriched among highly expressed transcription factor genes. Mutants defective in six transcription factor genes, three previously studied in detail (Rim101, Efg1, Zap1) and three less extensively studied (Rob1, Rpn4, Sut1), are profiled during infection. Most of these mutants have distinct gene expression profiles during infection as compared to in vitro growth. Infection profiles suggest that Sut1 acts in the same pathway as Zap1, and we verify that functional relationship with the finding that overexpression of either ZAP1 or the Zap1-dependent zinc transporter gene ZRT2 restores pathogenicity to a sut1 mutant. Perturbation with the cell wall inhibitor caspofungin also has distinct gene expression impact in vivo and in vitro. Unexpectedly, caspofungin induces many of the same genes that are repressed early during infection, a phenomenon that we suggest may contribute to drug efficacy. The pathogen response circuitry is tailored uniquely during infection, with many relevant regulatory relationships that are not evident during growth in vitro. Our findings support the principle that virulence is a property that is manifested only in the distinct environment in which host-pathogen interaction occurs.