Filamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression.
Filamentous fungal carbon catabolite repression supports metabolic plasticity and stress responses essential for disease progression.
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DOI：
10.1371/journal.ppat.1006340
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发表时间：
2017-04
期刊：
影响因子：
6.7
通讯作者：
Cramer RA
中科院分区：
文献类型：
--
作者：
Beattie SR;Mark KMK;Thammahong A;Ries LNA;Dhingra S;Caffrey-Carr AK;Cheng C;Black CC;Bowyer P;Bromley MJ;Obar JJ;Goldman GH;Cramer RA
与其他常见丝状真菌相比，烟曲霉是造成侵袭性真菌病病例不成比例的原因。虽然已知许多真菌因素对感染的建立至关重要，但对疾病持续和进展至关重要的基因尚未明确。我们认为真菌因子促进疾病进展中快速变化的营养和结构景观特征的导航，代表了尚未开发的临床相关治疗靶点。为此，我们发现烟曲霉需要碳分解代谢抑制（CCR）介导的遗传网络来支持体内真菌适应性和疾病进展。虽然由转录抑制因子CreA介导的CCR不是肺部感染建立所必需的，但CCR的缺失会抑制真菌的代谢可塑性和在动态感染微环境中茁壮成长的能力。我们的研究结果表明，环境丝状真菌中的CCR对于肺部感染的开始是必不可少的，但对于感染维持和疾病进展是必不可少的。从概念上讲，我们认为这些数据为支持真菌适应性和疾病进展所需的真菌因子的进一步研究提供了基础，并将这些基因和因子称为DPFs（疾病进展因子）。医学治疗的进步，如器官移植和抑制免疫系统的化疗，增加了易患侵袭性真菌疾病的患者数量。从这些感染中分离出的最常见的丝状真菌是环境霉菌，烟曲霉，侵袭性曲霉病（IA）的病原体。尽管进行了医疗干预，但IA的死亡率仍然很高，这表明需要了解烟曲霉的发病机制，以发现新的治疗靶点和策略。在这里，我们表明烟曲霉中央代谢的调节对感染维持和疾病进展至关重要。碳分解代谢物抑制的失调导致感染后期动物模型的毒力降低，因为无法驾驭感染微环境动力学，部分原因是缺氧和营养可用性的改变。这些结果可能不仅适用于IA，而且广泛适用于其他感染模型，强调需要了解个体微生物感染的时空动态，特别是在代谢水平上。我们建议支持疾病进展的微生物基因，与疾病起始相反，但并非相互排斥，被称为DPFs（疾病进展因子），因此代表了一类新的抗菌药物靶点。
Aspergillus fumigatus is responsible for a disproportionate number of invasive mycosis cases relative to other common filamentous fungi. While many fungal factors critical for infection establishment are known, genes essential for disease persistence and progression are ill defined. We propose that fungal factors that promote navigation of the rapidly changing nutrient and structural landscape characteristic of disease progression represent untapped clinically relevant therapeutic targets. To this end, we find that A. fumigatus requires a carbon catabolite repression (CCR) mediated genetic network to support in vivo fungal fitness and disease progression. While CCR as mediated by the transcriptional repressor CreA is not required for pulmonary infection establishment, loss of CCR inhibits fungal metabolic plasticity and the ability to thrive in the dynamic infection microenvironment. Our results suggest a model whereby CCR in an environmental filamentous fungus is dispensable for initiation of pulmonary infection but essential for infection maintenance and disease progression. Conceptually, we argue these data provide a foundation for additional studies on fungal factors required to support fungal fitness and disease progression and term such genes and factors, DPFs (disease progression factors). Medical treatment advances such as organ transplants and chemotherapies that suppress the immune system have increased the number of patients susceptible to invasive fungal diseases. The most common filamentous fungus isolated from these infections is the environmental mold, Aspergillus fumigatus, the causative agent of invasive aspergillosis (IA). Despite medical intervention, mortality from IA remains high, underscoring the need to understand A. fumigatus pathogenesis mechanisms to uncover new therapeutic targets and strategies. Here, we show that regulation of central metabolism in A. fumigatus is critical for infection maintenance and progression of disease. The dysregulation of carbon catabolite repression results in reduced virulence in an animal model at later stages of the infection because of an inability to navigate infection microenvironment dynamics driven in part by oxygen depletion and alterations in nutrient availability. These results likely not only apply to IA, but are broadly applicable to other infection models stressing the need to understand spatiotemporal dynamics of individual microbial infections particularly at the level of metabolism. We propose that microbial genes which support disease progression, in contrast but not mutually exclusive to disease initiation, be termed DPFs (disease progression factors) and as such represent a novel class of antimicrobial drug targets.