Nutritional Heterogeneity Among Aspergillus fumigatus Strains Has Consequences for Virulence in a Strain- and Host-Dependent Manner
Nutritional Heterogeneity Among Aspergillus fumigatus Strains Has Consequences for Virulence in a Strain- and Host-Dependent Manner
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DOI：
10.3389/fmicb.2019.00854
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发表时间：
2019-04-24
影响因子：
5.2
通讯作者：
Goldman, Gustavo H.
中科院分区：
文献类型：
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作者：
Annick Ries, Laure Nicolas;Steenwyk, Jacob L.;Goldman, Gustavo H.
不同碳源和氮源的获取和随后的代谢在真菌病原菌烟曲霉的毒力属性中起着重要的作用，如分泌宿主组织损伤蛋白酶和真菌细胞壁的完整性。我们研究了多种烟曲霉菌临床分离株的碳分解代谢抑制(CCR)和氮分解代谢抑制(NCR)代谢过程与毒力的关系。在中性粒细胞减少的肺曲霉菌病(PA)小鼠模型中，观察到相当多的CCR和NCR程度的异质性，并且NCR与毒力呈正相关。选择分离株Afs35进行进一步分析，并与参考菌株A1163进行比较，两株菌株在中性粒细胞减少的PA小鼠模型中表现出相同程度的毒力。在生理相关碳源中的Afs35代谢组分析表明，胞内糖类的积累也是细胞壁多糖的前体。基因组分析显示，在蛋白酶分泌调节器和编码细胞壁糖代谢所需的酶的基因中积累了错义替换。基于这些结果，在曲安奈德PA小鼠模型中评估了菌株Afs35和A1163的毒力，发现它们有显著的不同，证实了使用不同的小鼠模型来评估菌株特异性致病性的已知重要性。这些结果强调了氮代谢对毒力的重要性，并提供了一个详细的例子，说明了烟曲霉菌株之间存在的异质性，并以一种特定的和宿主相关的方式对毒力产生了影响。
Acquisition and subsequent metabolism of different carbon and nitrogen sources have been shown to play an important role in virulence attributes of the fungal pathogen Aspergillus fumigatus, such as the secretion of host tissue-damaging proteases and fungal cell wall integrity. We examined the relationship between the metabolic processes of carbon catabolite repression (CCR), nitrogen catabolite repression (NCR) and virulence in a variety of A. fumigatus clinical isolates. A considerable amount of heterogeneity with respect to the degree of CCR and NCR was observed and a positive correlation between NCR and virulence in a neutropenic mouse model of pulmonary aspergillosis (PA) was found. Isolate Afs35 was selected for further analysis and compared to the reference strain A1163, with both strains presenting the same degree of virulence in a neutropenic mouse model of PA. Afs35 metabolome analysis in physiological-relevant carbon sources indicated an accumulation of intracellular sugars that also serve as cell wall polysaccharide precursors. Genome analysis showed an accumulation of missense substitutions in the regulator of protease secretion and in genes encoding enzymes required for cell wall sugar metabolism. Based on these results, the virulence of strains Afs35 and A1163 was assessed in a triamcinolone murine model of PA and found to be significantly different, confirming the known importance of using different mouse models to assess strain-specific pathogenicity. These results highlight the importance of nitrogen metabolism for virulence and provide a detailed example of the heterogeneity that exists between A. fumigatus isolates with consequences for virulence in a strain-specific and host-dependent manner.