CHU de Québec Research Center (CHUQ), Université Laval, Quebec City, Quebec, Canada.
Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada.
mSphere. 2020 Feb 26;5(1):e00913-19. doi: 10.1128/mSphere.00913-19.
Hypoxia is the predominant condition that the human opportunistic fungus encounters in the majority of the colonized niches within the host. So far, the impact of such a condition on the overall metabolism of this important human-pathogenic yeast has not been investigated. Here, we have undertaken a time-resolved metabolomics analysis to uncover the metabolic landscape of fungal cells experiencing hypoxia. Our data showed a dynamic reprogramming of many fundamental metabolic pathways, such as glycolysis, the pentose phosphate pathway, and different metabolic routes related to fungal cell wall biogenesis. The lipidome was highly affected by oxygen depletion, with an increased level of free fatty acids and biochemical intermediates of membrane lipids, including phospholipids, lysophospholipids, sphingolipids, and mevalonate. The depletion of oxygen-dependent lipids such as ergosterol or phosphatidylcholine with longer and polyunsaturated lateral fatty acid chains was observed only at the later hypoxic time point (180 min). Transcriptomics data supported the main metabolic response to hypoxia when matched to our metabolomic profiles. The hypoxic metabolome reflected different physiological alterations of the cell wall and plasma membrane of under an oxygen-limiting environment that were confirmed by different approaches. This study provided a framework for future investigations to examine relevant hypoxic metabolic trajectories in fungal virulence and fitness within the host. A critical aspect of cell fitness is the ability to sense and adapt to variations in oxygen levels in their local environment. is an opportunistic yeast that is the most prevalent human fungal pathogen. While hypoxia is the predominant condition that encounters in most of its niches, its impact on fungal metabolism remains unexplored so far. Here, we provided a detailed landscape of the metabolome that emphasized the importance of many metabolic routes for the adaptation of this yeast to oxygen depletion. The fungal hypoxic metabolome identified in this work provides a framework for future investigations to assess the contribution of relevant metabolic pathways in the fitness of and other human eukaryotic pathogens with similar colonized human niches. As hypoxia is present at most of the fungal infection foci in the host, hypoxic metabolic pathways are thus an attractive target for antifungal therapy.
缺氧是人类机会性病原体在宿主中大多数定植部位遇到的主要条件。到目前为止，这种情况对这种重要的人类致病性酵母的整体代谢的影响尚未被研究。在这里，我们进行了时间分辨代谢组学分析，以揭示经历缺氧的真菌细胞的代谢景观。我们的数据显示，许多基本代谢途径，如糖酵解、戊糖磷酸途径和与真菌细胞壁生物发生有关的不同代谢途径，都发生了动态重编程。脂质体受到缺氧的强烈影响，游离脂肪酸和膜脂质的生化中间产物水平增加，包括磷脂、溶血磷脂、鞘脂和甲羟戊酸。只有在较晚的缺氧时间点（180 分钟）才观察到依赖氧气的脂质如麦角固醇或含有较长和多不饱和侧链脂肪酸的磷脂酰胆碱的耗竭。转录组学数据支持当与我们的代谢组学图谱匹配时对缺氧的主要代谢反应。缺氧代谢组反映了细胞在限氧环境下细胞壁和质膜的不同生理变化，这一点通过不同的方法得到了证实。这项研究为未来在宿主中检查真菌毒力和适应性相关的缺氧代谢轨迹提供了一个框架。细胞适应性的一个关键方面是能够感知和适应其局部环境中氧气水平的变化。是一种机会性酵母，是最常见的人类真菌病原体。虽然缺氧是 在其大多数生境中遇到的主要条件，但到目前为止，它对真菌代谢的影响仍未被探索。在这里，我们提供了 代谢组的详细景观，强调了许多代谢途径对这种酵母适应缺氧的重要性。这项工作中确定的真菌缺氧代谢组为未来的研究提供了一个框架，以评估相关代谢途径在 和其他具有类似定植人类小生境的人类真核病原体适应性中的贡献。由于宿主中大多数真菌感染病灶都存在缺氧，因此缺氧代谢途径是抗真菌治疗的一个有吸引力的目标。
